pyrimidinones and trametinib

pyrimidinones has been researched along with trametinib* in 860 studies

*trametinib: InChIKey: LIRYPHYGHXZJBZ-UHFFFAOYSA-N [MeSH]

*trametinib: InChIKey: LIRYPHYGHXZJBZ-UHFFFAOYSA-N [MeSH]

Reviews

67 review(s) available for pyrimidinones and trametinib

ArticleYear
Efficacy of Dabrafenib and Trametinib in a Patient with Squamous-Cell Carcinoma, with Mutation p.D594G in
    International journal of molecular sciences, 2023, Jan-07, Volume: 24, Issue:2

    The 3rd class of BRAF (B-Raf Proto-Oncogene, Serine/Threonine Kinase) variants including G466, D594, and A581 mutations cause kinase death or impaired kinase activity. It is unlikely that RAF (Raf Proto-Oncogene, Serine/Threonine Kinase) inhibitors suppress ERK (Extracellular Signal-Regulated Kinase) signaling in class 3 mutant-driven tumors due to the fact that they preferentially inhibit activated BRAF V600 mutants. However, there are suggestions that class 3 mutations are still associated with enhanced RAS/MAPK (RAS Proto-Oncogene, GTPase/Mitogen-Activated Protein Kinase) activation, potentially due to other mechanisms such as the activation of growth factor signaling or concurrent MAPK pathway mutations, e.g., RAS or NF1 (Neurofibromin 1). A 75-year-old male patient with squamous-cell cancer (SqCC) of the lung and with metastases to the kidney and mediastinal lymph nodes received chemoimmunotherapy (expression of Programmed Cell Death 1 Ligand 1 (PD-L1) on 2% of tumor cells). The chemotherapy was limited due to the accompanying myelodysplastic syndrome (MDS), and pembrolizumab monotherapy was continued for up to seven cycles. At the time of progression, next-generation sequencing was performed and a c.1781A>G (p.Asp594Gly) mutation in the BRAF gene, a c.1381C>T (p.Arg461Ter) mutation in the NF1 gene, and a c.37C>T (p.Gln13Ter) mutation in the FANCC gene were identified. Combined therapy with BRAF (dabrafenib) and MEK (trametinib) inhibitors was used, which resulted in the achievement of partial remission of the primary lesion and lung nodules and the stabilization of metastatic lesions in the kidney and bones. The therapy was discontinued after five months due to myelosuppression associated with MDS. The molecular background was decisive for the patient’s fate. NSCLC patients with non-V600 mutations in the BRAF gene rarely respond to anti-BRAF and anti-MEK therapy. The achieved effectiveness of the treatment could be related to a mutation in the NF1 tumor suppressor gene. The loss of NF1 function causes the excessive activation of KRAS and overactivity of the signaling pathway containing BRAF and MEK, which were the targets of the therapy. Moreover, the mutation in the FANCC gene was probably related to MDS development. The NGS technique was crucial for the qualification to treatment and the prediction of the NSCLC course in our patient. The mutations in two genes—the BRAF oncogene and the NF1 tumor suppressor gene—were the reason for the use of dabra

    Topics: Aged; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Extracellular Signal-Regulated MAP Kinases; Genes, Neurofibromatosis 1; Humans; Lung Neoplasms; Male; Mutation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Serine

2023
Interstitial lung disease associated with combination therapy of dabrafenib and trametinib in metastatic BRAF
    International journal of clinical pharmacology and therapeutics, 2022, Volume: 60, Issue:5

    Thyroid cancer is the most common malignancy of the endocrine system, accounting for ~ 5% of all thyroid nodules and 1% of all systemic malignancies.. We treated a 73-year-old man with metastatic. The mechanisms of lung disease after the combined treatment with dabrafenib and trametinib are unclear. We hypothesized that dual-targeted therapy with a BRAF inhibitor, dabrafenib, and a MEK inhibitor, trametinib, might prevent the regeneration and proliferation of fibrotic epithelium in lung disease by blocking downstream proliferative signals.

    Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Lung Diseases, Interstitial; Male; Mitogen-Activated Protein Kinase Kinases; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Neoplasms

2022
Sensitivity to dabrafenib and trametinib treatments in patients with non-small-cell cancer harboring BRAF compound mutations: A pooled analysis of BRAF p.V600E-positive advanced non-small-cell lung cancer.
    Cancer genetics, 2022, Volume: 266-267

    The present study clarified the sensitivity of the BRAF tyrosine kinase inhibitor mechanism in patients with BRAF compound mutation and predicted the sensitivity using molecular dynamics simulation.. We examined 16 BRAF tumors with p.V600E-positive non-small-cell lung cancer.. One patient (6.2%) had a BRAF p.V600E and p.K601_W604 compound mutation with a good clinical response to dabrafenib and trametinib. Molecular dynamics simulation also complemented the effect.. The combination of a genetic analysis and computational simulation model may help predict the sensitivity for dabrafenib in cases with a rare BRAF compound mutation. The construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2022
"RB-reactivator screening" as a novel cell-based assay for discoveries of molecular targeting agents including the first-in-class MEK inhibitor trametinib (trade name: Mekinist).
    Pharmacology & therapeutics, 2022, Volume: 236

    The retinoblastoma gene (RB) was discovered as the first tumor-suppressor gene. It was subsequently shown to be inactivated in most malignant tumors, particularly at the protein level. Therefore, many activated oncogenes as well as inactivated tumor-suppressor genes inactivate the function of the RB protein. I hypothesized that most of the molecular-targeting agents against activated oncogenes may reactivate the function of RB, and proposed screening systems for agents up-regulating the expression of cyclin-dependent kinase inhibitors, such as p15, p27, and p21, which convert the phosphorylated inactive form of the RB protein to the unphosphorylated active form. I termed this screening as "RB-reactivator screening". Using the screening systems for agents that up-regulate the expression of p15, p27, and p21, we discovered the novel MEK inhibitor trametinib, the novel RAF/MEK inhibitor CH5126766/RO5126766/VS-6766, and the histone deacetylase inhibitor YM753/OBP-801, respectively. Trametinib exerted remarkable effects in patients with advanced BRAF mutant melanoma, and was approved in the USA as the first-in-class MEK inhibitor (trade name: Mekinist) in 2013. The British Pharmacological Society selected trametinib as the Drug Discovery of the Year in 2013. The combination of trametinib and the BRAF inhibitor dabrafenib was approved for advanced BRAF mutant melanoma in the USA, EU, Japan, and many other countries. Additionally, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for the combination of trametinib and dabrafenib in the treatment of patients with advanced BRAF mutant non-small cell lung cancer in 2015, and this combination was subsequently approved in the EU, USA, and Japan. In 2018, this combination was also approved for locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer in the USA after it had been granted Breakthrough Therapy Designation by the FDA. I describe here the characterization of our original screening system, RB-reactivator screening, by which these three molecular-targeting agents that advanced into clinical trials were identified.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Drug Discovery; Humans; Lung Neoplasms; Melanoma; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinoblastoma Protein

2022
Durable Response to Trametinib in an Infant With
    JCO precision oncology, 2022, Volume: 6

    Topics: Fibrosarcoma; Humans; Infant; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2022
Rechallenge with dabrafenib plus trametinib in anaplastic thyroid cancer: A case report and review of literature.
    Current problems in cancer, 2021, Volume: 45, Issue:2

    Anaplastic thyroid carcinoma (ATC) is a highly aggressive, undifferentiated rare tumor. Median overall survival is usually between 8 and10 months, with a 1-year survival rate of 20%. Conventional anthracycline based chemotherapy regimens demonstrate low response rates with short duration. Novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape of ATC have been investigated.. We herein report the rechallenge of a 52-year-old ATC patient with BRAF V600E mutation with dabrafenib plus trametinib. She presented with recurrent and progressive disease despite surgery, radiation therapy, 3 different chemotherapy regimens, and combination of dabrafenib-trametinib in different settings. She was rechallenged with dabrafenib-trametinib, and had a good response.. To our knowledge, this is the first ATC case who responded to dabrafenib-trametinib rechallenge, reported in the literature. We want to emphasize that combination of dabrafenib and trametinib might be a good choice for resistant locoregional and metastatic ATC patients with BRAF V600E mutation, particularly in whom rapid clinical response is urgently needed. Moreover, rechallenge with this combination should be kept in mind in selected cases.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Middle Aged; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

2021
Approach in Improving Potency and Selectivity of Kinase Inhibitors: Allosteric Kinase Inhibitors.
    Mini reviews in medicinal chemistry, 2021, Volume: 21, Issue:8

    Allostery is an efficient and particular regulatory mechanism to regulate protein functions. Different from conserved orthosteric sites, allosteric sites have a distinctive functional mechanism to form the complex regulatory network. In drug discovery, kinase inhibitors targeting the allosteric pockets have received extensive attention for the advantages of high selectivity and low toxicity. The approval of trametinib as the first allosteric inhibitor validated that allosteric inhibitors could be used as effective therapeutic drugs for the treatment of diseases. To date, a wide range of allosteric inhibitors have been identified. In this perspective, we outline different binding modes and potential advantages of allosteric inhibitors. In the meantime, the research processes of typical and novel allosteric inhibitors are described briefly in terms of structure-activity relationships, ligand-protein interactions, and in vitro and in vivo activity. Additionally, challenges, as well as opportunities, are also presented.

    Topics: Allosteric Regulation; Humans; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Protein Kinases; Pyridones; Pyrimidinones; Structure-Activity Relationship

2021
Comparative efficacy and safety of adjuvant nivolumab versus other treatments in adults with resected melanoma: a systematic literature review and network meta-analysis.
    BMC cancer, 2021, Jan-05, Volume: 21, Issue:1

    Immune checkpoint inhibitors and targeted therapies are approved for adjuvant treatment of patients with resected melanoma; however, they have not been compared in randomized controlled trials (RCTs). We compared the efficacy and safety of adjuvant nivolumab with other approved treatments using available evidence from RCTs in a Bayesian network meta-analysis (NMA).. A systematic literature review was conducted through May 2019 to identify relevant RCTs evaluating approved adjuvant treatments. Outcomes of interest included recurrence-free survival (RFS)/disease-free survival (DFS), distant metastasis-free survival (DMFS), all-cause grade 3/4 adverse events (AEs), discontinuations, and discontinuations due to AEs. Time-to-event outcomes (RFS/DFS and DMFS) were analyzed both assuming that hazard ratios (HRs) are constant over time and that they vary.. Of 26 identified RCTs, 19 were included in the NMA following a feasibility assessment. Based on HRs for RFS/DFS, the risk of recurrence with nivolumab was similar to that of pembrolizumab and lower than that of ipilimumab 3 mg/kg, ipilimumab 10 mg/kg, or interferon. Risk of recurrence with nivolumab was similar to that of dabrafenib plus trametinib at 12 months, however, was lower beyond 12 months (HR [95% credible interval] at 24 months, 0.46 [0.27-0.78]; at 36 months, 0.28 [0.14-0.59]). Based on HRs for DMFS, the risk of developing distant metastases was lower with nivolumab than with ipilimumab 10 mg/kg or interferon and was similar to dabrafenib plus trametinib.. Adjuvant therapy with nivolumab provides an effective treatment option with a promising risk-benefit profile.

    Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Disease-Free Survival; Humans; Imidazoles; Ipilimumab; Melanoma; Nivolumab; Oximes; Patient Safety; Pyridones; Pyrimidinones

2021
Response to BRAF and MEK1/2 inhibition in a young adult with BRAF V600E mutant epithelioid glioblastoma multiforme: A Case Report and Literature Review.
    Current problems in cancer, 2021, Volume: 45, Issue:5

    Epithelioid glioblastoma multiforme (eGBM) is a rare and aggressive variant of glioblastoma multiforme (GBM) that predominantly affects younger patients and can be difficult to distinguish from other gliomas. Data on how patients with eGBM might be best treated are limited, although genomic analyses have shown that almost half of tumours harbour activating BRAF gene mutations. Here we present the case of a young female with BRAF V600E-mutant eGBM who had a prolonged response to targeted therapy with the BRAF and MEK1/2 inhibitors dabrafenib and trametinib. We review current knowledge about eGBM, including the emerging role for BRAF- ± MEK1/2- targeted therapy.

    Topics: Antineoplastic Agents; Brain Neoplasms; Fatal Outcome; Female; Glioblastoma; Humans; Imidazoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Spinal Cord Neoplasms; Young Adult

2021
Adjuvant Therapy of Melanoma.
    Hematology/oncology clinics of North America, 2021, Volume: 35, Issue:1

    as adjuvant therapy for high-risk melanoma was extensively studied in regimens that varied by dosage, route of administration, formulation, and therapy duration. The high-dose regimen (HDI) showed significant improvements in relapse-free survival (RFS) in 3 trials and overall survival (OS) in 2. Ipilimumab at 3 mg/kg demonstrated significant OS benefits compared with HDI and less toxicity compared with ipilimumab at 10 mg/kg. More recently, the standard of care has changed in favor of nivolumab and pembrolizumab and BRAF-MEK inhibitors dabrafenib plus trametinib (for BRAF mutated melanoma), based on significant RFS benefits and more favorable toxicity profiles.

    Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Humans; Imidazoles; Immunotherapy; Interferon-alpha; Ipilimumab; Lymph Node Excision; Melanoma; Nivolumab; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiotherapy, Adjuvant; Skin Neoplasms

2021
[Management of toxicities of BRAF inhibitors and MEK inhibitors in advanced melanoma].
    Bulletin du cancer, 2021, Volume: 108, Issue:5

    Major therapeutic advances have been made recently in the treatment of metastatic melanoma, due to the development of targeted therapies, namely BRAF and MEK inhibitors, in patients with BRAF V600 mutation. Combinations of vemurafenib+cobimetinib, dabrafenib+trametinib, et encorafenib+binimetinib, evaluated in coBRIM, COMBI-d/COMBI-v and COLUMBUS trials respectively have been approved in this indication. Toxicities induced by combination therapies are different from those reported with monotherapies, in terms of frequency and intensity. Physicians who treat melanoma patients thus face news issues relating to prevention, detection and treatment of these adverse events. This paper summarizes tolerance data from the three pivotal trials (coBRIM, COMBI-v and COLUMBUS) and issues recommendations for the specific management of main toxicities, based on experts' opinion. We discuss dermatological, ophthalmological, cardiovascular, digestive, musculoskeletal, renal and general toxicities and propose a timetable for examinations to be performed before and during treatment.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Drug Combinations; Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2021
Efficacy and safety of dabrafenib-trametinib in the treatment of unresectable advanced/metastatic melanoma with BRAF-V600 mutation: A systematic review and network meta-analysis.
    Dermatologic therapy, 2020, Volume: 33, Issue:2

    The current systematic review aimed to evaluate and compare the efficacy and safety of dabrafenib-trametinib with those of other therapeutic alternatives in the treatment of patients with unresectable advanced/metastatic melanoma with BRAF-V600 mutation. The search was carried out on four databases up to July 2018. Two separate network meta-analyses (NMA) were performed using the frequentist method (random effects): one with an exclusive population with BRAF-V600 mutation (NMA-pBRAFV600) and another with mixed population (with or without the mutation: NMA-pMixed). An evidence profile was included using the GRADE method for NMA. The validity of the final estimator in the NMA-pMixed was assessed via a sensitivity analysis. Nine clinical trials were included in the NMA-pBRAFV600. Dabrafenib-trametinib was found to have a favorable effect on overall survival (OS) and progression-free survival (PFS) compared with dabrafenib, vemurafenib, and dacarbazine and on partial response rate (PRR) and overall response rate compared with dacarbazine and vemurafenib. In the NMA-pMixed, dabrafenib-trametinib was found to have a positive effect on OS versus ipilimumab 3 mg/kg and on PFS and PRR versus ipilimumab, nivolumab, and pembrolizumab. However, dabrafenib-trametinib and vemurafenib-cobimetinib significantly differed in terms of efficacy. In addition, dabrafenib-trametinib has a favorable effect on Grades 3 and 4 adverse events.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Network Meta-Analysis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2020
Symptomatic neurocutaneous melanosis: mild clinical onset in a teenager.
    BMJ case reports, 2020, Nov-30, Volume: 13, Issue:11

    Neurocutaneous melanosis (NCM) is a rare disorder characterised by giant or multiple melanocytic nevi and meningeal melanosis or melanoma. Onset of neurological symptoms is typically in children younger than 2 years and can be rapidly fatal. We present the case of a 13-year-old adopted girl presenting with numerous congenital melanocytic nevi and a seizure. She had no significant previous neurological history. Electroencephalogram showed epileptiform discharges over the right frontal region. MRI of the brain showed T1 hyperintensity in the bilateral amygdala and anterior temporal lobes with corresponding hyperintensity on T2 and fluid attenuated inversion recovery. There was no hydrocephalus. Along with the history of nevi, these imaging findings were concerning for NCM. The patient is being managed with levetiracetam and trametinib and shows no further neurological decline at 1-year follow-up, providing prognostic hope in this case of NCM.

    Topics: Adolescent; Amygdala; Anticonvulsants; Electroencephalography; Female; Humans; Levetiracetam; Magnetic Resonance Imaging; Male; Melanosis; Mitogen-Activated Protein Kinase Kinases; Neurocutaneous Syndromes; Nevus, Pigmented; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Seizures; Temporal Lobe

2020
A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma.
    European journal of cancer (Oxford, England : 1990), 2019, Volume: 123

    Although a myriad of novel treatments entered the treatment paradigm for advanced melanoma, there is lack of head-to-head evidence. We conducted a network meta-analysis (NMA) to estimate each treatment's relative effectiveness and safety.. A systematic literature review (SLR) was conducted in Embase, MEDLINE and Cochrane to identify all phase III randomised controlled trials (RCTs) with a time frame from January 1, 2010 to March 11, 2019. We retrieved evidence on treatment-related grade III/IV adverse events, progression-free survival (PFS) and overall survival (OS). Evidence was synthesised using a Bayesian fixed-effect NMA. Reference treatment was dacarbazine. In accordance with RCTs, dacarbazine was pooled with temozolomide, paclitaxel and paclitaxel plus carboplatin. To increase homogeneity of the study populations, RCTs were only included if patients were not previously treated with novel treatments.. The SLR identified 28 phase III RCTs involving 14,376 patients. Nineteen and seventeen treatments were included in the effectiveness and safety NMA, respectively. For PFS, dabrafenib plus trametinib (hazard ratio [HR] PFS: 0.21) and vemurafenib plus cobimetinib (HR PFS: 0.22) were identified as most favourable treatments. Both had, however, less favourable safety profiles. Five other treatments closely followed (dabrafenib [HR PFS: 0.30], nivolumab plus ipilimumab [HR PFS: 0.34], vemurafenib [HR PFS: 0.38], nivolumab [HR PFS: 0.42] and pembrolizumab [HR PFS: 0.46]). In contrast, for OS, nivolumab plus ipilimumab (HR OS: 0.39), nivolumab (HR OS: 0.46) and pembrolizumab (HR OS: 0.50) were more favourable than dabrafenib plus trametinib (HR OS: 0.55) and vemurafenib plus cobimetinib (HR OS: 0.57).. Our NMA identified the most effective treatment options for advanced melanoma and provided valuable insights into each novel treatment's relative effectiveness and safety. This information may facilitate evidence-based decision-making and may support the optimisation of treatment and outcomes in everyday clinical practice.

    Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Cancer Vaccines; Carboplatin; Dacarbazine; gp100 Melanoma Antigen; Humans; Hydrazines; Imidazoles; Interleukin-2; Ipilimumab; Lenalidomide; Melanoma; Network Meta-Analysis; Nitrosourea Compounds; Nivolumab; Organophosphorus Compounds; Oximes; Paclitaxel; Piperidines; Progression-Free Survival; Proportional Hazards Models; Pyridones; Pyrimidinones; Skin Neoplasms; Sorafenib; Survival Rate; Temozolomide; Treatment Outcome; Vemurafenib

2019
Trametinib in the treatment of multiple malignancies harboring MEK1 mutations.
    Cancer treatment reviews, 2019, Volume: 81

    The aberrant activation of RAS-derived mitogen-activated protein kinase (MAPK) signaling pathway plays a prominent role in tumorigenesis of an array of malignancies. The reasons are usually the upstream activated mutations including mitogen-activated protein kinase kinase 1/2 (MEK1/2). As oncogenic mutations, MEK1 mutations have been observed in a variety of malignancies including melanoma, histiocytic neoplasms, colorectal cancer and lung cancer. Presently, the use of trametinib, a highly selective MEK1/2 inhibitor, was limited to BRAF mutations, according to the approvals of FDA. Therefore, we consider that this is a question worth studying that whether malignancies with MEK1 mutations are sensitive to the treatment of trametinib. This review discussed the function of MEK1 mutations, retrieved the frequency and distribution of MEK1 mutations in various malignancies, and reviewed the basic experiments and clinical case reports on trametinib in the treatment of cell lines or patients with MEK1 mutations. Most studies have demonstrated that trametinib was effective to cells or tumor patients harboring MEK1 mutations, which suggest that the MEK1 mutations might be potential indications of trametinib therapy. In addition, it was also reported that resistance was observed in the treatment of trametinib, suggesting that different MEK1 mutations may have different response to trametinib, and further studies are necessary to distinguish that which MEK1 mutations are appropriate for the treatment with trametinib and which are not.

    Topics: Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Asian People; Histiocytosis, Langerhans-Cell; Humans; Liver Neoplasms; Lung Neoplasms; MAP Kinase Kinase 1; Mice; Mutation; Neoplasms; NIH 3T3 Cells; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2019
Comparative efficacy and safety of dabrafenib in combination with trametinib versus competing adjuvant therapies for high-risk melanoma.
    Journal of comparative effectiveness research, 2019, Volume: 8, Issue:16

    Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Imidazoles; Interferons; Ipilimumab; Male; Melanoma; Middle Aged; Neoplasm Recurrence, Local; Network Meta-Analysis; Nivolumab; Oximes; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Skin Neoplasms; Treatment Outcome; Vemurafenib

2019
Therapeutic potential of trametinib to inhibit the mutagenesis by inactivating the protein kinase pathway in non-small cell lung cancer.
    Expert review of anticancer therapy, 2019, Volume: 19, Issue:1

    Topics: Animals; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; MAP Kinase Signaling System; Molecular Targeted Therapy; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones

2019
Network meta-analysis of therapies for previously untreated advanced BRAF-mutated melanoma.
    Cancer treatment reviews, 2019, Volume: 74

    The spectrum of treatment options for patients with metastatic BRAF-mutated melanoma is broad, spanning multiple treatment classes. However, there is a lack of head-to-head evidence comparing targeted and immunotherapies. The purpose of this study is to conduct a network meta-analysis (NMA) in previously untreated, BRAF-mutated melanoma patients and estimate the relative efficacy of systemic therapies for this patient population at the treatment level.. The literature review included searches of MEDLINE, EMBASE, and the Cochrane Central Registry of Controlled Trials (CENTRAL) to November 2018. Randomized controlled trials of previously untreated patients with advanced melanoma were eligible if at least one intervention was either a targeted or immune therapy. Relative treatment effects were estimated by fixed effect Bayesian NMAs on progression-free survival (PFS) and overall survival (OS), based on the hazard ratio.. Combination dabrafenib with trametinib (HR 0.22 [95% CrI 0.17, 0.28] vs dacarbazine) and combination vemurafenib with cobimetinib (HR 0.22 [95% CrI 0.17, 0.29] vs dacarbazine) were likely to rank as the most favorable treatment options for PFS, while combination nivolumab with ipilimumab was likely to be the most efficacious in terms of OS (HR 0.33 [0.24, 0.47] vs dacarbazine).. The findings highlight the efficacy of combination PD-1 with CTLA-4 inhibitors and combination BRAF with MEK inhibitors in the treatment of advanced melanoma. However, as few trials informed each treatment comparison, research is needed to further refine our understanding of this complex and rapidly evolving treatment landscape.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Dacarbazine; Humans; Imidazoles; Melanoma; Molecular Targeted Therapy; Mutation; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Vemurafenib

2019
The extent of surgery for stage III melanoma: how much is appropriate?
    The Lancet. Oncology, 2019, Volume: 20, Issue:3

    Since the first documented lymph node dissection in 1892, many trials have investigated the potential effect of this surgical procedure on survival in patients with melanoma. Two randomised controlled trials were unable to demonstrate improved survival with completion lymph node dissection versus nodal observation in patients with sentinel node-positive disease, although patients with larger sentinel node metastases (>1 mm) might benefit more from observation than from dissection, and could potentially be considered for adjuvant systemic therapy instead of complete dissection. Adjuvant immunotherapy with high-dose ipilimumab has led to improvements in overall survival, whereas therapy with nivolumab and pembrolizumab has improved relapse-free survival with greater safety. Furthermore, adjuvant-targeted therapy with dabrafenib and trametinib has improved survival outcomes in BRAF

    Topics: Chemotherapy, Adjuvant; Disease-Free Survival; Humans; Imidazoles; Ipilimumab; Lymph Node Excision; Lymph Nodes; Melanoma; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2019
Disseminated intravascular coagulation and melanoma: a novel case occurring in metastatic melanoma with BRAF and NRAS mutations and systematic review.
    Melanoma research, 2019, Volume: 29, Issue:5

    Disseminated intravascular coagulation is a complex and potentially lethal complication of malignancy, in which the fundamental abnormality is excessive activation of the coagulation system. It is a rare complication of melanoma which can be difficult to diagnose in some circumstances, leading to delay in treatment. Herein, we describe the first case of disseminated intravascular coagulation occurring in BRAF and NRAS-mutant metastatic melanoma, and systematically review the literature regarding disseminated intravascular coagulation in melanoma. This review summarizes the reported cases of disseminated intravascular coagulation in melanoma and those secondary to the novel treatment of melanoma, and explores the pathophysiology of disseminated intravascular coagulation in melanoma, highlighting the key role of expression of markers of coagulation and fibrinolysis in disseminated intravascular coagulation, as well as more widely in melanoma. Current limitations in the literature are also identified and discussed, particularly with respect to improving the management of this lethal complication. Disseminated intravascular coagulation is a rare complication of melanoma that typically portends poor prognosis.

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation; Disseminated Intravascular Coagulation; Female; Fibrinolysis; GTP Phosphohydrolases; Humans; Imidazoles; Melanoma; Membrane Proteins; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2019
The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma.
    Expert opinion on drug safety, 2018, Volume: 17, Issue:1

    The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment. Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings. Additionally, published case series/case reports were screened for information on AEs. Expert opinion: Even though almost every patient (98%) under combination therapy with dabrafenib and trametinib experiences at least one adverse event, these are generally mild to moderate, reversible and can be managed with dose reductions or interruptions. However, due to an increased life expectancy, there is a substantial need to prevent and treat also mild adverse events, as they play a central role for the quality of life of patients. Ongoing clinical trials will have to demonstrate the efficacy as well as safety of triple combination with anti-PD-1/anti-PD-L1 antibodies.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Humans; Imidazoles; Melanoma; Oximes; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Quality of Life; Skin Neoplasms

2018
Melanoma in 2017: Moving treatments earlier to move further forwards.
    Nature reviews. Clinical oncology, 2018, Volume: 15, Issue:2

    Topics: Clinical Trials, Phase III as Topic; Humans; Imidazoles; Immunotherapy; Lymphatic Metastasis; Melanoma; Neoplasm Staging; Oximes; Progression-Free Survival; Pyridones; Pyrimidinones; Sentinel Lymph Node

2018
Targeted therapy for infants with diencephalic syndrome: A case report and review of management strategies.
    Pediatric blood & cancer, 2018, Volume: 65, Issue:5

    Young children with emaciation caused by a hypothalamic glioma are considered to have diencephalic syndrome (DS), which is often poorly controlled with conventional treatment. We describe an infant with DS whose tumor progressed following chemotherapy. Biopsy was performed for molecular testing and demonstrated a BRAF fusion. Treatment with the MEK inhibitor trametinib for 18 months resulted in reduction of tumor size, normalization of his weight curve, and marked neurodevelopmental improvement. Our results build on earlier reports of using targeted agents for low-grade glioma, and we review the evolving management strategy for such patients in the era of precision medicine.

    Topics: Disease Management; Humans; Hypothalamic Diseases; Infant; Male; Molecular Targeted Therapy; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridones; Pyrimidinones

2018
Targeting few to help hundreds: JAK, MAPK and ROCK pathways as druggable targets in atypical chronic myeloid leukemia.
    Molecular cancer, 2018, 02-19, Volume: 17, Issue:1

    Atypical Chronic Myeloid Leukemia (aCML) is a myeloproliferative neoplasm characterized by neutrophilic leukocytosis and dysgranulopoiesis. From a genetic point of view, aCML shows a heterogeneous mutational landscape with mutations affecting signal transduction proteins but also broad genetic modifiers and chromatin remodelers, making difficult to understand the molecular mechanisms causing the onset of the disease. The JAK-STAT, MAPK and ROCK pathways are known to be responsible for myeloproliferation in physiological conditions and to be aberrantly activated in myeloproliferative diseases. Furthermore, experimental evidences suggest the efficacy of inhibitors targeting these pathways in repressing myeloproliferation, opening the way to deep clinical investigations. However, the activation status of these pathways is rarely analyzed when genetic mutations do not occur in a component of the signaling cascade. Given that mutations in functionally unrelated genes give rise to the same pathology, it is tempting to speculate that alteration in the few signaling pathways mentioned above might be a common feature of pathological myeloproliferation. If so, targeted therapy would be an option to be considered for aCML patients.

    Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Humans; Janus Kinases; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Mitogen-Activated Protein Kinases; Mutation; Nitriles; Pyrazoles; Pyridones; Pyrimidines; Pyrimidinones; rho-Associated Kinases; Signal Transduction

2018
Uveitis and serous retinal detachment secondary to systemic dabrafenib and trametinib.
    Archivos de la Sociedad Espanola de Oftalmologia, 2018, Volume: 93, Issue:9

    The case is presented of a 39-year-old woman with metastatic melanoma treated with dabrafenib and trametinib. She presented with a severe acute panuveitis with granulomatous anterior uveitis, vitritis, and multiple serous retinal detachments. Dabrafenib and trametinib were suspended, and treatment with a systemic and topical corticosteroid was started. A good response was obtained, with a recovery of visual acuity of 1.0 in both eyes within two weeks.. Dabrafenib and trametinib can lead to severe uveitis. Treatment with corticosteroids and discontinuation of therapy with dabrafenib and trametinib led to an anatomical and functional improvement, and resolved the episode rapidly. Ophthalmologists must be aware of this toxicity, given the increasing use of those drugs.

    Topics: Adrenal Cortex Hormones; Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Synergism; Fatal Outcome; Female; Humans; Imidazoles; MAP Kinase Kinase Kinases; Melanoma; Neoplasm Proteins; Oximes; Panuveitis; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Detachment; Vemurafenib

2018
Dabrafenib and trametinib for the treatment of non-small cell lung cancer.
    Expert review of anticancer therapy, 2018, Volume: 18, Issue:11

    Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2018
Management of Treatment-Related Adverse Events with Agents Targeting the MAPK Pathway in Patients with Metastatic Melanoma.
    The oncologist, 2017, Volume: 22, Issue:7

    Tremendous progress has been made in the clinical landscape of advanced-stage. Targeted therapy with BRAF plus MEK inhibitors has become the standard of care for patients with advanced-stage

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Fever; Humans; Imidazoles; Indoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Diseases; Sulfonamides; Vemurafenib

2017
MEK Inhibitors in the Treatment of Metastatic Melanoma and Solid Tumors.
    American journal of clinical dermatology, 2017, Volume: 18, Issue:6

    The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines. MEK inhibitor therapy in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for patients with BRAF-mutated melanoma. Trametinib was the first MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors, and is also approved in combination with the BRAF inhibitor dabrafenib. Furthermore, cobimetinib is another MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma in combination with a BRAF inhibitor, vemurafenib. The MEK inhibitor binimetinib in combination with the BRAF inhibitor encorafenib is in clinical development. The addition of an anti-PD-1/PD-L1 agent, such as pembrolizumab, durvalumab or atezolizumab, to combined BRAF and MEK inhibition has shown considerable promise, with several trials ongoing in metastatic melanoma. Binimetinib has also shown efficacy in NRAS-mutated melanoma patients. Future possibilities for MEK inhibitors in advanced melanoma, as well as other solid tumors, include their use in combination with other targeted therapies (e.g. anti-CDK4/6 inhibitors) and/or various immune-modulating antibodies.

    Topics: Humans; MAP Kinase Kinase 1; Melanoma; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2017
Interaction of molecular alterations with immune response in melanoma.
    Cancer, 2017, 06-01, Volume: 123, Issue:S11

    Major advances have been made in melanoma treatment with the use of molecularly targeted therapies and immunotherapies, and numerous regimens are now approved by the US Food and Drug Administration for patients with stage IV disease. However, therapeutic resistance remains an issue to both classes of agents, and reliable biomarkers of therapeutic response and resistance are lacking. Mechanistic insights are being gained through preclinical studies and translational research, offering potential strategies to enhance responses and survival in treated patients. A comprehensive understanding of the immune effects of common mutations at play in melanoma is critical, as is an appreciation of the molecular mechanisms contributing to therapeutic resistance to immunotherapy. These mechanisms and the interplay between them are discussed herein. Cancer 2017;123:2130-42. © 2017 American Cancer Society.

    Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; CTLA-4 Antigen; Drug Resistance, Neoplasm; GTP Phosphohydrolases; Humans; Imidazoles; Immunotherapy; Indoles; Ipilimumab; MAP Kinase Kinase 1; Melanoma; Membrane Proteins; Molecular Targeted Therapy; Mutation; Nivolumab; Oximes; Programmed Cell Death 1 Receptor; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Tumor Escape; Vemurafenib; Wnt Signaling Pathway

2017
The new paradigm of systemic therapies for metastatic melanoma.
    Journal of the American Academy of Dermatology, 2017, Volume: 77, Issue:2

    New treatments for metastatic melanoma work through distinct mechanisms: enhancing the immune response and blocking cellular proliferation. Agents that enhance the immune response include ipilimumab, pembrolizumb, and nivolumab; agents that block cellular proliferation include vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, and selumetinib. The translational impact of laboratory discoveries has revolutionized management of metastatic melanoma and enhanced the prognosis of affected patients.

    Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Humans; Imidazoles; Immunologic Factors; Indoles; Ipilimumab; Melanoma; Molecular Targeted Therapy; Nivolumab; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

2017
Cardiovascular Effects of the MEK Inhibitor, Trametinib: A Case Report, Literature Review, and Consideration of Mechanism.
    Cardiovascular toxicology, 2017, Volume: 17, Issue:4

    The MEK inhibitor trametinib was approved in 2013 for the treatment of unresectable or metastatic melanoma with a BRAF V600E mutation, the most common pathogenic mutation in melanoma. Trametinib blocks activation of ERK1/2, inhibiting cell proliferation in melanoma. ERK1/2 also protects against multiple types of cardiac insult in mouse models. Trametinib improves survival in melanoma patients, but evidence of unanticipated cardiotoxicity is emerging. Here we describe the case of a patient with metastatic melanoma who developed acute systolic heart failure after trametinib treatment and present the results of the literature review prompted by this case. A patient with no cardiac history presented with a 6.5-mm skin lesion and was found to have metastatic BRAF V600E melanoma. Combination treatment with trametinib and the BRAF inhibitor, dabrafenib, was initiated. The patient's pre-treatment ejection fraction was 55-60%. His EF declined after 13 days and that was 40% 1 month after treatment. Two months after initiating trametinib, he developed dyspnea and fatigue. We conducted a chart review in the electronic medical record. We conducted a PubMed search using trametinib/adverse effects AND ("heart failure" OR "left ventricular dysfunction" OR hypertension OR cardiotoxicity OR mortality). We also queried the FDA Adverse Events Reporting System for reports of cardiomyopathy, ejection fraction decrease, and left ventricular dysfunction associated with trametinib between January 1, 2013, and July 20, 2017. The literature search retrieved 19 articles, including clinical trials and case reports. Early clinical experience with the MEK inhibitor trametinib suggests that its clinical efficacy may be compromised by cardiotoxicity. Further studies in humans and animals are required to determine the extent of this adverse effect, as well as its underlying mechanisms.

    Topics: Aged; Heart Failure; Humans; Male; Melanoma; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Stroke Volume

2017
Recent Progress in Mutation-driven Therapy, Immunotherapy and Combination Therapy for the Treatment of Melanoma.
    Current cancer drug targets, 2017, Volume: 17, Issue:2

    With increases in our understanding of the human genome and immune system, the treatment armamentarium for melanoma has benefitted from the development and approval of BRAF inhibitors, MEK inhibitors, immune checkpoint modulators via cytotoxic T-lymphocyte antigen-4 blockade, and PD-1 and PD-L1 inhibitors. These advances, however, have raised questions about combination therapy, the optimal sequential use of these agents, the limited assessment of response using traditional metrics, and the optimal selection of the population to be treated. In this review we summarize recent breakthroughs and then itemize the development of newer agents, potential prognostic and predictive biomarkers, resistance mechanisms, and strategies of combination therapy. We also emphasize the multifaceted attributes of immunotherapy in terms of durable responses and longterm survival that paradoxically necessitate further research into the underlying mechanisms and longer patient follow-up.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; CTLA-4 Antigen; Drug Resistance, Neoplasm; Humans; Imidazoles; Immunotherapy; Indoles; Melanoma; Mutation; Oximes; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2017
Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas.
    Pharmacological research, 2017, Volume: 117

    The Ras-Raf-MEK-ERK (Map kinase) cellular pathway is a highly conserved eukaryotic signaling module that transduces extracellular signals from growth factors and cytokines into intracellular regulatory events that are involved in cell growth and proliferation or the contrary pathway of cell differentiation. Dysregulation of this pathway occurs in more than one-third of all malignancies, a process that has fostered the development of targeted Map kinase pathway inhibitors. Cutaneous melanomas, which arise from skin melanocytes, are the most aggressive form of skin cancer. Mutations that activate the Map kinase pathway occur in more than 90% of these melanomas. This has led to the development of the combination of dabrafenib and trametinib or vemurafenib and cobimetanib for the treatment of BRAF V600E mutant melanomas. Dabrafenib and vemurafenib target V600E/K BRAF mutants while trametinib and cobimetanib target MEK1/2. The latter two agents bind to MEK1/2 at a site that is adjacent to, but separate from, the ATP-binding site and are therefore classified as type III allosteric protein kinase inhibitors. These agents form a hydrogen bond with a conserved β3-lysine and they make numerous hydrophobic contacts with residues within the αC-helix, the β5 strand, and within the activation segment, regions of the protein kinase domain that exhibit greater diversity than those found within the ATP-binding site. One advantage of such allosteric inhibitors is that they do not have to compete with millimolar concentrations of cellular ATP, which most FDA-approved small molecule competitive inhibitors such as imatinib must do. Owing to the wide spread activation of this pathway in numerous neoplasms, trametinib and cobimetinib are being studied in combination with other targeted and cytotoxic drugs in a variety of clinical situations. Except for BRAF and NRAS mutations, there are no other biomarkers correlated with treatment responses following MEK1/2 inhibition and the discovery of such biomarkers would represent an important therapeutic breakthrough.

    Topics: Antineoplastic Agents; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Melanoma, Cutaneous Malignant; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

2017
Trametinib (MEKINIST°) Metastatic or inoperable BRAF V600-positive melanoma: a few extra months of life.
    Prescrire international, 2016, Volume: 25, Issue:177

    About 50% of patients with meta- static or inoperable melanoma carry a tumour with BRAF V600 mutation.The drug of first choice for these patients is vemurafenib, a BRAF inhibitor, which appears to prolong survival by a few months. Dabrafenib is a vemurafenib me-too with a slightly different known profile of adverse effects. Trametinib, a MEK inhibitor, is now authorised in the European Union for use in this setting, either as monotherapy or in combination with dabrafenib (marketed by the same company). Trametinib monotherapy has not been compared to BRAF inhibitor monotherapy. In a randomised, unblinded trial versus cytotoxic drugs in 322 patients, the median survival time did not differ statistically between the groups (15.6 versus 11.3 months; p = 0.09), but 65% of patients in the chemotherapy group received trametinib after disease pro- gression, making it more difficult to detect a difference between the groups. In an unblinded randomised controlled trial in 704 patients who had never received treatment for metastatic or inoperable disease, the trametinib + dabrafenib combination prolonged median survival by about 8 months more than vemurafenib. In another double-blind randomised controlled trial in 423 patients, median survival was about 6 months longer with trametinib + dabrafenib than with placebo + dabrafenib. The trametinib+ dabrafenibcombination was poorly effective after BRAF inhibitor failure in non-comparative trials including a few dozen patients in which the only endpoint was tumour response. Trametinib has many adverse effects, some of which can be life-threatening, such as heart failure, deep vein thrombosis, bleeding (including intracranial haemorrhage), neutropenia, and gastrointestinal perforation. Trametinib also causes retinal disorders and pneumonitis. Combining trametinib with dabrafenib reduces the risk of hyperkeratosis and skin cancer associated with dabrafenib, but increases the frequency of fever (including very high fever). Trametinib interactions mainly involve additive effects or antagonism. In practice, when a patient with metastatic or inoperable BRAF V600-positive melanoma is willing to accept the significant toxicity of trametinib in the hope of gaining several extra months of life, the trametinib + dabrafenib combination is a first-line option.

    Topics: Heart Failure; Hemorrhage; Humans; Imidazoles; Intestinal Perforation; Intracranial Hemorrhages; MAP Kinase Kinase 1; Melanoma; Neutropenia; Oximes; Pneumonia; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Diseases; Skin Neoplasms; Survival Rate; Venous Thrombosis

2016
The Future of Molecular Analysis in Melanoma: Diagnostics to Direct Molecularly Targeted Therapy.
    American journal of clinical dermatology, 2016, Volume: 17, Issue:1

    Melanoma is a malignancy of pigment-producing cells that is driven by a variety of genetic mutations and aberrations. In most cases, this leads to upregulation of the mitogen-activated protein kinase (MAPK) pathway through activating mutations of upstream mediators of the pathway including BRAF and NRAS. With the advent of effective MAPK pathway inhibitors, including the US FDA-approved BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitor trametinib, molecular analysis has become an integral part of the care of patients with metastatic melanoma. In this article, the key molecular targets and strategies to inhibit these targets therapeutically are presented, and the techniques of identifying these targets, in both tissue and blood, are discussed.

    Topics: DNA Mutational Analysis; GTP Phosphohydrolases; Humans; Imidazoles; Indoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Melanoma; Membrane Proteins; Molecular Diagnostic Techniques; Molecular Targeted Therapy; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

2016
Treatment of melanoma brain metastases.
    Current opinion in oncology, 2016, Volume: 28, Issue:2

    Melanoma has a tendency to metastasize to the brain. The development of brain metastasis is observed in all mutational subgroups. Overall, they are associated with poor prognosis. They are also associated with pain, neurological deterioration and thus, have a major impact on patients' quality of life. Historically, effective palliation by systemic therapy has been rare. The availability of new therapeutic agents, however, heralds a significant improvement in management options for these patients.. The development of targeted therapies and immune activating checkpoint inhibitors with durable benefit has led to a treatment paradigm change. Several clinical studies in patients with metastatic melanoma have demonstrated improved survival compared to chemotherapy. Many of these studies however excluded patients with brain involvement. Antitumor activity in brain metastasis has now been observed with some agents; further positive data are emerging. Surgery and stereotactic radiotherapy are also used for local control of oligometastatic disease. We discuss the usefulness of the available systemic treatments for management of brain metastases and how these are integrated with local treatments to enable optimal palliation.. Advances in the treatment of melanoma are providing significant palliative benefit for patients with brain metastases. Further investigations are needed to determine optimal treatment combinations and sequences.

    Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Disease-Free Survival; Humans; Immunotherapy; Indoles; Melanoma; Molecular Targeted Therapy; Nivolumab; Prognosis; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Quality of Life; Skin Neoplasms; Sulfonamides; Vemurafenib

2016
Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations.
    Expert opinion on pharmacotherapy, 2016, Volume: 17, Issue:7

    In the 40-50% of advanced melanoma patients with tumors harboring BRAF V600E and V600 K mutations, BRAF inhibitors such as dabrafenib are a highly effective treatment. However, most patients develop resistance after several months on treatment. The addition of a MEK inhibitor, such as trametinib, to BRAF inhibition mitigates one key pathway of resistance, further increasing response rates and improving survival.. This article summarizes the mechanism of action of the combination of dabrafenib and trametinib, its evolution through Phase I, II and III clinical trials and discusses its current use in the management of patients with advanced melanoma.. Combination therapy with dabrafenib and trametinib improves response rate, progression-free survival and overall survival when compared to dabrafenib or vemurafenib alone. The addition of trametinib to dabrafenib changes the adverse event profile, making hyperkeratosis and cutaneous squamous cell carcinomas less common but side effects such as fever and nausea more common. How dabrafenib/trametinib is best sequenced with other effective treatments such as immune checkpoint blockade remains uncertain.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Fever; Humans; Imidazoles; MAP Kinase Signaling System; Melanoma; Mutation; Nausea; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2016
The relative clinical efficacy of trametinib-dabrafenib and cobimetinib-vemurafenib in advanced melanoma: an indirect comparison.
    Journal of clinical pharmacy and therapeutics, 2016, Volume: 41, Issue:3

    Melanoma causes the majority of skin cancer-related deaths. The outcome of melanoma depends on its stage at diagnosis. Currently, for patients with advanced melanoma, two MEK inhibitors (trametinib and cobimetinib) have been authorized by the European Medicines Agency. The main objective of this study was to compare the relative efficacy of trametinib-dabrafenib and cobimetinib-vemurafenib in patients with advanced melanoma through adjusted indirect treatment comparisons (ITCs).. A search was made up to the 3rd of November 2015. Databases consulted were MEDLINE, the Cochrane Library and the Centre for Reviews and Dissemination. Randomized controlled trials (RCTs) which compared the efficacy of trametinib-dabrafenib or cobimetinib-vemurafenib versus a common treatment comparator, in which outcomes of overall survival, progression-free survival (PFS) and overall response rate (ORR) were considered. ITCs were carried out using the method proposed by Bucher et al.. Two RCTs were included (one for each drugs combination). The results of the adjusted ITCs showed that there were no statistically significant differences between the two combinations in terms of PFS and ORR.. The ITCs indicate no difference in efficacy between both treatments. However, there should be an independent, head-to-head trial of both combinations to confirm the results.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Disease-Free Survival; Humans; Imidazoles; Indoles; Melanoma; Neoplasm Staging; Oximes; Piperidines; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Skin Neoplasms; Sulfonamides; Survival Rate; Treatment Outcome; Vemurafenib

2016
Dabrafenib plus Trametinib: a Review in Advanced Melanoma with a BRAF (V600) Mutation.
    Targeted oncology, 2016, Volume: 11, Issue:3

    The BRAF inhibitor dabrafenib (Tafinlar(®)) and the MEK inhibitor trametinib (Mekinist(®)) are indicated, as monotherapy or in combination with each other, for the treatment of patients with unresectable or metastatic melanoma with a BRAF (V600) mutation. This article reviews the therapeutic efficacy and tolerability of combination treatment with dabrafenib and trametinib in this indication and summarizes relevant pharmacological data. Dabrafenib plus trametinib significantly prolonged progression-free survival (PFS) and overall survival (OS), improved objective response rates (ORRs) and preserved health-related quality of life (HR-QOL) to a greater extent than dabrafenib (in the double-blind COMBI-d study) and vemurafenib (in the open-label COMBI-v study) in two large, randomized, phase III studies in treatment-naïve patients with unresectable or metastatic melanoma with BRAF (V600E/K) mutation. Limited treatment benefit with the combination was also seen in patients who had progressed on prior BRAF inhibitor therapy, as indicated by ORRs of ≤ 15 % and stable disease in ≤ 50 % of patients in small phase I and II studies. Combination therapy did not increase overall toxicity relative to dabrafenib or vemurafenib monotherapy, with most adverse events (AEs) mild or moderate in severity and generally manageable. Fewer skin-related AEs (e.g. cutaneous malignancies, hyperkeratinosis and hand-foot syndrome) were reported with combination therapy than with dabrafenib or vemurafenib, probably because of reduced paradoxical activation of the MAPK pathway. Thus, dabrafenib plus trametinib provides an important treatment option for patients with BRAF (V600) mutation-positive unresectable or metastatic melanoma.

    Topics: Antineoplastic Agents; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2016
Novel melanoma therapies and their side effects.
    Cutis, 2016, Volume: 97, Issue:6

    In the last few years, melanoma treatment has been revolutionized by the development of immune checkpoint-blocking antibodies or immune checkpoint inhibitors including ipilimumab, vemurafenib, dabrafenib, trametinib, nivolumab, and pembrolizumab. Although they have shown promising results, they also have caused multiple adverse events (AEs), particularly immune-related AEs (irAEs). Specialists should be familiar with these AEs.

    Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Drug Eruptions; Gastrointestinal Diseases; Humans; Hypophysitis; Hypothyroidism; Imidazoles; Immunosuppressive Agents; Indoles; Ipilimumab; Melanoma; Mycophenolic Acid; Nivolumab; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Sweet Syndrome; Thyrotoxicosis; Tumor Necrosis Factor-alpha; Vemurafenib; Vitiligo

2016
[Treatment of BRAF-mutated metastatic melanoma].
    Ugeskrift for laeger, 2016, Aug-29, Volume: 178, Issue:35

    Melanoma is an aggressive form of skin cancer which is the cause of a great number of skin cancer-related deaths worldwide and about 300 deaths in Denmark. After several years of failure of treatment of metastatic melanoma, the development of BRAF- and later MEK inhibitors was considered revolutionary. Treatment with BRAF inhibitors alone and especially in combination with a MEK inhibitor improves outcome for patients with BRAF V600-mutated metastatic melanoma. However, even when treated with the combination of the inhibitors, many patients develop acquired resistance within a year.

    Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2016
Metastatic rhabdoid meningioma with BRAF V600E mutation and good response to personalized therapy: case report and review of the literature.
    Pediatric hematology and oncology, 2015, Volume: 32, Issue:3

    Rhabdoid meningioma is an aggressive phenotype of meningioma, associated with a poor prognosis. We present a very rare case of high-grade meningioma with rhabdoid features that eventually expressed in a coma state. Comprehensive genomic profiling using a Next Generation Sequencing (NGS) assay revealed three genomic alterations: activating BRAF mutation (V600E), loss of CDKN2A/2B, and APC I1307K. After treatment with BRAF inhibitor (dabrafenib), the child's clinical condition improved progressively. After seven months, an MEK inhibitor was added (trametinib).

    Topics: Adenomatous Polyposis Coli Protein; Antineoplastic Agents; Child; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Female; Gene Expression Profiling; High-Throughput Nucleotide Sequencing; Humans; Imidazoles; Magnetic Resonance Imaging; Meningeal Neoplasms; Meningioma; Mutation; Oximes; Precision Medicine; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Rhabdoid Tumor

2015
Dabrafenib in combination with trametinib for the treatment of metastatic melanoma.
    Expert review of clinical pharmacology, 2015, Volume: 8, Issue:1

    Oncogenic BRAF mutations are present in approximately 40-50% of patients with metastatic melanoma. Targeting BRAF mutations with either small molecule inhibitors of BRAF or one of the downstream mediators of oncogenic BRAF - MEK - is associated with improved outcomes compared with chemotherapy and has led to the US FDA approval of two BRAF inhibitors - vemurafenib and dabrafenib - and the MEK inhibitor trametinib. Further, the combination of dabrafenib and trametinib is well tolerated and associated with higher responses and improved survival compared with single-agent BRAF inhibitors.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Imidazoles; Melanoma; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic

2015
Trametinib: a novel signal transduction inhibitor for the treatment of metastatic cutaneous melanoma.
    American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 2015, Jan-15, Volume: 72, Issue:2

    The pharmacology, pharmacokinetics, clinical efficacy, safety, administration, cost, and place in therapy of trametinib for the treatment of metastatic melanoma are reviewed.. Approximately 40-60% of malignant melanomas have gene mutations at codon 600 of the BRAF gene that result in the activation of the mitogen-activated protein kinase (MAPK) pathway. Trametinib is the first-in-class mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that targets a kinase in the MAPK pathway that plays a key role in oncogenic cell proliferation, survival, invasion, tumor angiogenesis, and escape from apoptosis. It is approved by the Food and Drug Administration for use in patients whose tumors express the BRAF V600E or V600K gene mutations. Moreover, trametinib is also indicated for use in combination with dabrafenib (a BRAF inhibitor). Trametinib is not indicated in patients who have received prior BRAF-inhibitor therapy due to poor response and possible cross-resistance. The most common adverse effects associated with the use of trametinib for both monotherapy and combination therapy are rash, diarrhea, peripheral edema, fatigue, and dermatitis. The recommended dosage of trametinib monotherapy is 2 mg orally once daily until disease progression or unacceptable toxicity occurs. With a daily dose of 2 mg, an estimated 30-day course of treatment would cost approximately $9135.. Trametinib, a novel MEK inhibitor, provides an alternative therapy for patients with BRAF V600 E/K metastatic melanoma as a single agent or in combination therapy for patients not previously treated with a BRAF inhibitor. More studies are needed to determine the safe and effective combination or sequencing of trametinib with other therapies.

    Topics: Animals; Antineoplastic Agents; Humans; MAP Kinase Signaling System; Melanoma; Melanoma, Cutaneous Malignant; Pyridones; Pyrimidinones; Signal Transduction; Skin Neoplasms

2015
Targeting of MEK in lung cancer therapeutics.
    The Lancet. Respiratory medicine, 2015, Volume: 3, Issue:4

    The MAP-kinase pathway, consisting of the kinases RAS, RAF, MEK, and ERK, is crucial for cell proliferation, inhibition of apoptosis, and migration of cells. Direct inhibition of RAS is not yet possible, whereas inhibition of RAF is already established in malignant melanoma and under investigation in non-small-cell lung cancer (NSCLC). Due to their structure and function, the MEK proteins are attractive targets for cancer therapy and are also under investigation in NSCLC. We discuss strategies of targeting the RAS-RAF-MEK-ERK pathway with emphasis on MEK inhibition, either alone or in combination with other targets or conventional chemotherapy.

    Topics: Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Extracellular Signal-Regulated MAP Kinases; Humans; Lung Neoplasms; Molecular Targeted Therapy; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones

2015
Trametinib in the treatment of melanoma.
    Expert opinion on biological therapy, 2015, Volume: 15, Issue:5

    Aberrant MAPK pathway signaling is a hallmark of melanoma. Mitogen/extracellular signal-regulated kinase (MEK) 1/2 are integral components of MAPK signaling. Several MEK inhibitors have demonstrated activity as single agents and in combination with other therapies. Trametinib was the first MEK inhibitor approved for use in treatment of advanced BRAF(V600) mutant melanoma as a single agent and in combination with BRAF inhibitor, dabrafenib.. In this article, we discuss the underlying biology of MEK inhibition and its rationale in melanoma treatment with special emphasis on the clinical development of trametinib, from initial Phase I studies to randomized Phase II and III studies, both as monotherapy and in combination with other therapeutics. Furthermore, we briefly comment on trametinib for NRAS mutant and other non-BRAF mutant subsets of melanoma.. Trametinib is a novel oral MEK inhibitor with clinical activity in BRAF(V600) mutant metastatic melanoma alone and in combination with dabrafenib. Trametinib is currently being explored in other genetic subsets as well, particularly those with NRAS mutations or atypical BRAF alterations. Furthermore, to maximize efficacy and overcome acquired resistance, studies evaluating the combination of trametinib with other targeted agents and immunotherapy are underway.

    Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Immunotherapy; Melanoma; Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Treatment Outcome

2015
Combined BRAF and MEK inhibition for the treatment of BRAF-mutated metastatic melanoma.
    Cancer treatment reviews, 2015, Volume: 41, Issue:6

    Combined BRAF and MEK inhibition out-performed BRAF inhibitor monotherapy in 3 randomized Phase 3 studies for BRAF-mutated metastatic melanoma patients and the combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib is now an FDA-approved treatment in this setting. Nevertheless, the majority of patients face progressive disease even when treated with the combination. Mechanisms of resistance to BRAF inhibition have been extensively investigated, whilst less is known about the specific mechanisms of resistance to combined therapy. The aim of this paper is to review the efficacy and safety of the combination of BRAF plus MEK inhibitors compared with BRAF inhibitor monotherapy and immunotherapy, as well as to discuss the existing evidence for the mechanisms of resistance to combined therapy and assess future treatment strategies to improve outcome based on data provided by clinical and translational research studies.

    Topics: Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2015
Dermatology update: The dawn of targeted treatment.
    Cleveland Clinic journal of medicine, 2015, Volume: 82, Issue:5

    During the past several years, targeted therapies have significantly improved outcomes in advanced basal cell carcinoma, psoriasis, and metastatic melanoma. This article reviews how advances in our understanding of the molecular pathogenesis of these diseases led to the development of targeted therapies and how these therapies are improving outcomes. Research is ongoing to address continuing challenges of drug resistance, adverse effects, and how best to use the new medications.

    Topics: Adult; Anilides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azetidines; Brain Neoplasms; Carcinoma, Basal Cell; Dermatologic Agents; Dermatology; Etanercept; Female; Humans; Imidazoles; Indoles; Interleukin-17; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Psoriasis; Pyridines; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Tumor Necrosis Factor-alpha; Ustekinumab; Vemurafenib

2015
Trametinib in metastatic melanoma.
    Expert review of anticancer therapy, 2015, Volume: 15, Issue:7

    The treatment of metastatic melanoma is rapidly changing. In 2002, the BRAF mutation was described in over 50% of melanomas and led to the first BRAF inhibitor, vemurafenib, being approved for clinical use in 2011. Clinical responses are often rapid but duration of response is limited due to the development of resistance. MEK is the next downstream target from BRAF in the MAP kinase pathway. Trametinib was the first MEK inhibitor to be approved for clinical use in 2013. Preclinical studies demonstrated a delay in resistance and a reduction in cutaneous toxicity by combined BRAF and MEK inhibition. Here, we review the rationale for clinical development of trametinib and give an update on recent clinical trials of trametinib alone and in combination with braf inhibition in melanoma.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; MAP Kinase Kinase 1; Melanoma; Molecular Targeted Therapy; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2015
Evolution of melanocytic nevi under vemurafenib, followed by combination therapy with dabrafenib and trametinib for metastatic melanoma.
    Acta dermatovenerologica Croatica : ADC, 2015, Volume: 23, Issue:2

    Treatment of advanced melanoma with selective BRAF and MEK inhibitors is associated with a series of mucocutaneous side effects, among which morphological changes in preexisting nevi and the development of new melanocytic lesions, both benign and malignant. Objective was to describe the changes observed in melanocytic nevi under vemurafenib therapy, followed by combination therapy with dabrafenib and trametinib for metastatic melanoma. The melanocytic lesions of a 51-year-old Caucasian male patient diagnosed with stage IV melanoma were monitored both clinically and dermoscopically throughout vemurafenib, followed by combined treatment with dabrafenib and trametinib. The 65 monitored nevi presented different behaviors under vemurafenib treatment: 18 reticular nevi, 9 reticular-homogenous nevi, 3 reticular-globular nevi, and 2 globular nevi showed a diffuse decrease in pigmentation. Ten reticular nevi remained unchanged, while the rest of the nevi, independent of the dermoscopic pattern, presented a gradual increase in pigmentation. On the other hand, under dabrafenib and trametinib treatment 57 of these nevi showed gradual decrease in pigmentation and central involution, while 7 reticular nevi and 1 globular nevus remained unchanged; none of the monitored nevi increased in pigmentation nor presented new globules following this combination therapy. Systematic total body skin examination is mandatory in patients receiving BRAF inhibitors. The divergent course of melanocytic nevi during vemurafenib vs. dabrafenib and trametinib therapy remains to be elucidated by further research.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Dermoscopy; Disease Progression; Follow-Up Studies; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Neoplasm Invasiveness; Nevus, Pigmented; Oximes; Pyridones; Pyrimidinones; Risk Assessment; Skin Neoplasms; Sulfonamides; Treatment Outcome; Vemurafenib

2015
Future of combination therapy with dabrafenib and trametinib in metastatic melanoma.
    Expert opinion on pharmacotherapy, 2015, Volume: 16, Issue:14

    Combination therapy with BRAF and MEK inhibitors is a recommended treatment strategy for metastatic melanoma patients with BRAF(V600) mutations. This treatment provides significant response rates and little added toxicity, with relatively improved survival outcomes compared to RAF/MEK inhibitor monotherapy and chemotherapy.. This review covers the pharmacology, efficacy, and toxicity data derived from clinical studies of dabrafenib, trametinib , and the combination thereof. The major downfall of combiDT is the limited durability of response, which is largely due to acquired resistance in the MAPK pathway.. Future directions of combiDT concentrate on further combinations with immunotherapy or other targeted inhibitors, referred to triple-agent therapy, which may be essential to improving durability of responses and overcoming resistance.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2015
Targeting the RAS pathway by mitogen-activated protein kinase inhibitors.
    Swiss medical weekly, 2015, Volume: 145

    Targeting of oncogenic driver mutations with small-molecule inhibitors resulted in powerful treatment options for cancer patients in recent years. The RAS (rat sarcoma) pathway is among the most frequently mutated pathways in human cancer. Whereas targeting mutant Kirsten RAS (KRAS) remains difficult, mutant B rapidly accelerated fibrosarcoma (BRAF) kinase is an established drug target in cancer. Now data show that neuroblastoma RAS (NRAS) and even Harvey RAS (HRAS) mutations could be predictive markers for treatment with mitogen-activated protein kinase (MEK) inhibitors. This review discusses recent preclinical and clinical studies of MEK inhibitors in BRAF and RAS mutant cancer.

    Topics: Animals; Azetidines; Benzamides; Benzimidazoles; Diphenylamine; Genes, ras; GTP Phosphohydrolases; Humans; Membrane Proteins; Mice; Mitogen-Activated Protein Kinases; Mutation; Neoplasms; Niacinamide; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Signal Transduction; Sulfonamides

2015
The role of MEK inhibitors in the treatment of metastatic melanoma.
    Current opinion in oncology, 2014, Volume: 26, Issue:2

    BRAF and NRAS mutations can exert an oncogenic effect and are a target for novel therapeutic strategies. Selective MEK inhibitors inhibit growth and induce cell death in BRAF and NRAS mutated melanoma cell lines. The first MEK inhibitor (trametinib) has recently been approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors and several more are in clinical development.. MEK inhibition is associated with improved response rate, progression-free survival, and overall survival in patients with BRAF-mutated metastatic melanoma. Less clinical benefit has been observed in patients previously treated with a BRAF inhibitor compared with BRAF-inhibitor-naïve patients. Data also suggest clinical activity in patients with NRAS-mutated melanoma. Combination therapy with a BRAF inhibitor may improve the efficacy and reduce BRAF-inhibition-associated side effects.. MEK inhibitors represent a new treatment option in BRAF and NRAS mutated melanoma. As monotherapy, MEK inhibitors appear to provide minimal benefit in patients previously treated with a BRAF inhibitor, so they should be reserved for BRAF-inhibitor-naïve patients. Combined BRAF and MEK inhibition seems to provide a greater benefit than BRAF inhibitor monotherapy. MEK inhibition has also shown efficacy in NRAS-mutated patients, for whom there is no specific targeted therapy.

    Topics: GTP Phosphohydrolases; Humans; MAP Kinase Kinase 1; Melanoma; Membrane Proteins; Mutation; Neoplasm Metastasis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

2014
Prospects for MEK inhibitors for treating cancer.
    Expert opinion on drug safety, 2014, Volume: 13, Issue:4

    The MAPK pathway is a signaling network that plays a key role in many normal cellular processes and in a large number of human malignancies. One of its effectors, MEK, is essential for the carcinogenesis of different tumors. In recent years, several drugs able to inhibit MEK have been assessed in clinical trials. Trametinib has recently become the first MEK inhibitor licensed for cancer treatment (advanced melanoma).. We comprehensively review the safety and clinical efficacy of the family of MEK inhibitors, either alone or in combination with other drugs. We discuss data ranging from the Phase III trial of trametinib in melanoma to the most recent drugs with early signs of antitumor activity. In addition, we explain the reasons for the unsuccessful results of the early trials with MEK inhibitors and provide a view of their role in cancer treatment in forthcoming years.. MEK inhibitors are a potentially safe and active treatment option for the treatment of many human malignancies. The information provided by a large series of studies currently ongoing will be very valuable in order to optimize their use. Adequate selection of patients is crucial for achieving successful results with these compounds.

    Topics: Antineoplastic Agents; Clinical Trials, Phase III as Topic; Humans; MAP Kinase Kinase 1; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2014
Trametinib.
    Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer, 2014, Volume: 201

    The mitogen-activated protein kinase (MEK MAPK/ERK kinase) signaling pathways play a critical role in regulation of diverse cellular activities, including survival, differentiation, proliferation, motility, and angiogenesis. Therefore, MEK inhibition was recognized as a promising target for antineoplastic therapy. While multiple MEK inhibitors have been tested clinically only trametinib (GSK1120212), an oral MEK inhibitor which is selective for MEK1 and MEK2 has shown promising activity in several clinical trials on melanoma and colorectal cancer and it is being evaluated by the FDA for the treatment of metastatic melanoma. Mechanistically it was shown that trametinib induces cell cycle arrest in vitro. In this overview, important preclinical and clinical data for trametinib are presented including mechanism-based in vitro studies as well as findings from different clinical studies. Future clinical trial in different solid tumor entities will define the therapeutic role of this targeted therapy approach, possibly as a combination with other targeted therapies such as BRAF inhibitors.

    Topics: Animals; Antineoplastic Agents; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Pyridones; Pyrimidinones

2014
Managing the skin toxicities from new melanoma drugs.
    Current treatment options in oncology, 2014, Volume: 15, Issue:2

    Patients treated with ipilimumab or targeted inhibitors of the RAF-MEK-ERK pathway (vemurafenib, dabrafenib, and trametinib) for advanced cutaneous melanoma often experience drug-related skin toxicities denoted as dermatologic adverse events (DAEs). Although rarely life-threatening, DAEs may emerge dramatically and potentially compromise oncologic therapy if not managed in a timely and effective manner. Early recognition of DAEs is critical to providing optimal skin care and prompt consultation with a dermatologist should be obtained when a diagnosis is unclear. The expanding utilization of new melanoma drugs compels physicians to maintain a watchful eye for both known and novel DAEs and to adopt a low threshold to biopsy worrisome skin findings. Numerous therapeutic options are available to manage DAEs including topical and systemic agents as well as surgical and destructive modalities. Applying such methods improves overall patient care and optimizes the effectiveness of new therapies for advanced cutaneous melanoma.

    Topics: Antibodies, Monoclonal; Antineoplastic Agents; Humans; Imidazoles; Indoles; Inflammation; Ipilimumab; Melanoma; Melanoma, Cutaneous Malignant; Oximes; Pyridones; Pyrimidinones; Skin; Skin Diseases; Skin Neoplasms; Sulfonamides; Treatment Outcome; Vemurafenib

2014
Dabrafenib for the treatment of BRAF V600-positive melanoma: a safety evaluation.
    Expert opinion on drug safety, 2014, Volume: 13, Issue:9

    V-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors are emerging as the standard of care for treating advanced melanomas harboring the BRAF V600 oncogenic mutation. Dabrafenib is the second approved selective BRAF inhibitor (after vemurafenib) for the treatment of unresectable or metastatic BRAF V600-positive melanoma.. This review covers the current data on the efficacy and safety of the selective BRAF inhibitor dabrafenib in patients with metastatic BRAF V600 positive melanoma. The pharmacological, safety and efficacy data are discussed from Phase I, II, and III studies of dabrafenib monotherapy as well as in combination with the MEK inhibitor trametinib.. Dabrafenib has demonstrated comparable efficacy to vemurafenib in BRAF V600E mutant melanoma patients. Dabrafenib is well tolerated in patients with metastatic melanoma, including patients with brain metastases. Nevertheless side effects are common, but usually manageable. In the Phase III study testing dabrafenib, 53% of patients reported grade 2 or higher adverse events (AEs). Toxicities were similar to those seen in the early-phase trials, with the most common being cutaneous manifestations (hyperkeratosis, papillomas, palmar-plantar erythrodysesthesia), pyrexia, fatigue, headache, and arthralgia. Combining a BRAF inhibitor with a MEK inhibitor, which may block paradoxical MAPK activation in BRAF wild type (skin) cells, may lower the incidence of squamoproliferative eruptions.

    Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2014
Controversies in the management of advanced melanoma: "gray" areas amid the "black and blue".
    The Annals of pharmacotherapy, 2014, Volume: 48, Issue:11

    To examine the current controversies and discuss consensus recommendations regarding treatment sequencing and the role of BRAF inhibitor at disease progression.. An English-language literature search of MEDLINE/PubMed (1966-May 2014), using the keywords advanced melanoma, ipilimumab, cytotoxic T-lymphocyte antigen 4, dabrafenib, vemurafenib, BRAF inhibitor, trametinib, MEK inhibitor, and treatment sequencing was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries.. All relevant published articles and abstracts on ipilimumab, vemurafenib, dabrafenib, and trametinib were reviewed. Clinical trial registries and meeting abstracts were used for ongoing studies.. The availability of new agents has made therapy selection more complex. Immunotherapy supporters reason that immunotherapy offers the best chance for long-term benefit and does not compromise the antitumor activity of subsequent BRAF inhibitors. Targeted therapy advocates rely on the high probability and rapid onset of response to BRAF inhibitors. Currently, there is insufficient evidence regarding the role of BRAF inhibitor at disease progression.. Therapy should be individualized based on patient- and disease-specific factors. Immunotherapy represents the best option for durable remission; however, targeted therapy is more appropriate for patients who are symptomatic or have rapidly growing tumors. The novel therapies have also demonstrated meaningful intracranial activity; thus, the presence of brain metastases should be taken into consideration in selecting therapy. Limited data exist about the continuation of BRAF inhibitors after therapeutic failure. Active research is ongoing to define the best option for patients with BRAF inhibitor refractory disease.

    Topics: Antibodies, Monoclonal; Antineoplastic Agents; CTLA-4 Antigen; Drug Resistance, Neoplasm; Humans; Imidazoles; Immunotherapy; Indoles; Ipilimumab; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

2014
Current systemic therapies for melanoma.
    Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.], 2014, Volume: 40, Issue:9

    Systemic agents are used in melanoma for adjuvant therapy and to treat metastatic disease. Currently, interferon-α is the only agent approved for adjuvant therapy. Six drugs are FDA approved for metastatic disease: dacarbazine, interleukin-2 (IL-2), vemurafenib, ipilimumab, dabrafenib, and trametinib. Vemurafenib and ipilimumab were approved in 2011, whereas dabrafenib and trametinib were approved in 2013.. This review will update the practicing dermatologist on the differences in efficacy, adverse events, and cost of systemic therapies available for the treatment of melanoma.. This article is a review of the current literature on systemic therapies for advanced melanoma. Key search words included "advanced melanoma," "systemic therapy," and "adjuvant therapy" with particular focus on the past 20 years.. Before 2011, dacarbazine and IL-2 were the only FDA approved therapies for metastatic melanoma, and IFN-α is the only approved agent for adjuvant therapy. The new agents vemurafenib, ipilimumab, dabrafenib, and trametinib are the first to have improved overall survival in Phase III studies in comparison with other systemic therapies.. Despite new developments, there remains a significant need for better therapies with improved long-term efficacy and decreased toxicity.

    Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Bridged-Ring Compounds; Dacarbazine; Humans; Imidazoles; Indoles; Interferon-alpha; Interleukin-2; Ipilimumab; Melanoma; Oximes; Platinum Compounds; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Taxoids; Temozolomide; Vemurafenib

2014
Role of the MEK inhibitor trametinib in the treatment of metastatic melanoma.
    Future oncology (London, England), 2014, Volume: 10, Issue:9

    Approximately 50% of patients with cutaneous metastatic melanoma harbor a somatic BRAF mutation. BRAF inhibitors are now established in the treatment paradigm of BRAF mutant melanoma, following the approval of vemurafenib by the US FDA in 2011. The vast majority of patients obtain some degree of tumor shrinkage with oral BRAF inhibitors, and responses are often rapid. However, resistance inevitably develops, with a median progression-free survival of 5-7 months. The oral MEK inhibitor trametinib has also shown activity in BRAF mutant melanoma in Phase III trials. We review the rationale for treating BRAF mutant melanoma with trametinib, as single-agent therapy and in combination with BRAF inhibitors, as well as the clinical data to date.

    Topics: Antineoplastic Agents; Clinical Trials as Topic; Disease-Free Survival; Humans; Kaplan-Meier Estimate; MAP Kinase Kinase Kinases; Melanoma; Mutation, Missense; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2014
[Targeted molecular therapies (except immunotherapy)].
    Bulletin du cancer, 2014, Volume: 101 Suppl 2

    Metastatic melanoma has been a very poor prognostic cancer with a median of survival between six to eight months. A lot of new therapies have been discovered these last years. Two types of treatment have emerged: immunotherapy and targeted therapy. Targeted therapies have been developed because of the discovery of new oncogenic mutations with a big impact of melanoma development. The efficacy is great with a high overall response and a good tolerance. However, most of patients escape in few months of targeted therapy. The sequence of drug using and their combination are the question for the next years.

    Topics: Antineoplastic Agents; Humans; Imidazoles; Indoles; MAP Kinase Kinase Kinase 1; Melanoma; Molecular Targeted Therapy; Neoplasm Proteins; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

2014
Trametinib (GSK1120212) in the treatment of melanoma.
    Expert opinion on pharmacotherapy, 2013, Volume: 14, Issue:5

    The discovery of somatic mutations in melanoma has advanced our knowledge of the biology of the disease. The mutations, such as those in NRAS, BRAF, GNAQ and GNA11, promote the growth of melanoma cells in most part through the mitogen-activated protein kinase (MAPK) pathway. Understanding the molecular pathways of some of these mutations has resulted in the successful development of selective BRAF inhibitors. Yet, a cure for advanced melanoma is far from reality. Targeting MAPK/ERK kinase (MEK), an essential intermediary kinase protein within the MAPK pathway, may be a promising way to treat patients with BRAF or other genomic mutation.. The authors discuss the MAPK pathway in melanoma and review the preclinical and clinical studies of the MEK inhibitor, trametinib , in melanoma. They also discuss the potential of using trametinib in the targeted therapy of advanced melanoma.. Studies have demonstrated the activity of trametinib in BRAF-mutant melanoma, suggesting that it could be a very reasonable alternative to BRAF inhibitors for these patients. Current clinical investigations have shown great promise with the combination of trametinib and dabrafenib in patients with BRAF-mutant melanoma; a number of clinical trials of trametinib in combination with other targeted drugs are underway.

    Topics: Animals; Antineoplastic Agents; Humans; MAP Kinase Signaling System; Melanoma; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2013
Ipilimumab, vemurafenib, dabrafenib, and trametinib: synergistic competitors in the clinical management of BRAF mutant malignant melanoma.
    The oncologist, 2013, Volume: 18, Issue:6

    There have been significant advances in the treatment of malignant melanoma with the U.S. Food and Drug Administration approval of two drugs in 2011, the first drugs approved in 13 years. The developments of immune checkpoint modulation via cytotoxic T-lymphocyte antigen-4 blockade, with ipilimumab, and targeting of BRAF(V600), with vemurafenib or dabrafenib, as well as MEK, with trametinib, have been paradigm changing both for melanoma clinical practice and for oncology therapeutic development. These advancements, however, reveal new clinical questions regarding combinations and optimal sequencing of these agents in patients with BRAF mutant disease. We review the development of these agents, putative biomarkers, and resistance mechanisms relevant to their use, and possibilities for sequencing and combining these agents.

    Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Drug Synergism; Humans; Imidazoles; Indoles; Ipilimumab; MAP Kinase Kinase Kinases; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2013
Advances in the systemic treatment of metastatic melanoma.
    Oncology (Williston Park, N.Y.), 2013, Volume: 27, Issue:5

    Prior to 2011, the only commercially available agents commonly used to treat metastatic melanoma-including dacarbazine, temozolomide (Temodar), fotemustine, carboplatin, paclitaxel, and interleukin-2-demonstrated limited efficacy, and no study involving these agents had shown an improvement in overall survival. The standard of care for the treatment of metastatic melanoma was radically changed by the subsequent approval of two agents, ipilimumab (Yervoy) and vemurafenib (Zelboraf), both of which improved survival in randomized phase III trials. Within the relatively short time that ipilimumab and vemurafenib have been commercially available, phase II data for the investigational agents nivolumab and MK-3475, for the combination of dabrafenib and trametinib, and for adoptive cell therapy strongly suggest even further improvements in treatment outcomes. Within this rich context of effective agents, the challenge for clinicians and investigators will be to develop predictive biomarkers of response, the optimal sequence of therapy for individual patients, and effective combinations. An additional challenge will be to find the appropriate venue and populations to test promising new agents arising from substantial advances in our understanding of molecular alterations in melanoma cells, of mechanisms of resistance to current agents, and of tumor-host immune interactions.

    Topics: Antibodies, Monoclonal; Drug Therapy, Combination; Humans; Imidazoles; Immunologic Factors; Immunotherapy, Adoptive; Indoles; Ipilimumab; Melanoma; Mutation; Nivolumab; Oximes; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

2013
Resistance to BRAF-targeted therapy in melanoma.
    European journal of cancer (Oxford, England : 1990), 2013, Volume: 49, Issue:6

    BRAF mutations are identified in 40-50% of patients with melanoma. Treatment of these patients with either of two BRAF inhibitors (vemurafenib, dabrafenib) or the MEK inhibitor trametinib is associated with improved clinical benefit (response rate, progression free survival, and overall survival) compared with treatment with chemotherapy in three phase III trials. Unfortunately, most patients, including those who experience initial, profound tumour regression, have evidence of disease progression within 6-8 months after commencing therapy with one of these agents. The mechanisms of resistance are varied and include activation of alternative signalling pathways as well as reactivating the MAP kinase pathway through alternative means. This review describes relevant aspects of MAP kinase pathway signalling, summarises the clinical data with BRAF and MEK inhibitors, presents the known resistance mechanisms to BRAF inhibitor therapy, and provides some strategies for how resistance may be overcome.

    Topics: Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Imidazoles; Indoles; MAP Kinase Signaling System; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2013
[Progress of research and development of MAPK pathway inhibitors].
    Nihon yakurigaku zasshi. Folia pharmacologica Japonica, 2013, Volume: 141, Issue:1

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Drug Discovery; Humans; Imidazoles; Indoles; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Neoplasms; Oximes; Pyridones; Pyrimidinones; raf Kinases; Research; Sulfonamides; Vemurafenib

2013
Which drug, and when, for patients with BRAF-mutant melanoma?
    The Lancet. Oncology, 2013, Volume: 14, Issue:2

    Patients with metastatic melanoma had few treatment options until 2011, when two drugs-ipilimumab and vemurafenib-were approved following advances in the understanding of melanoma biology and tumour immunology. Almost 50% of melanomas harbour mutations in BRAF, mainly at codon 600, which result in constitutive activation of the MAPK pathway. The selective inhibitors of mutant BRAF Val600, vemurafenib and dabrafenib, showed major tumour responses, resulting in improved progression-free and overall survival in patients with metastatic disease, compared with chemotherapy. Antitumour activity was also recorded in brain metastases. The growth of cutaneous squamous-cell carcinomas is a unique side-effect of BRAF inhibitor therapy that is induced by the paradoxical activation of the MAPK pathway in cells with RAS mutations. Trametinib, which targets MEK downstream of BRAF, also produced an overall survival benefit compared with chemotherapy, although tumour responses were less frequent than they were with BRAF inhibitors. Despite this robust antitumour activity, most responses to these drugs are partial and disease progression is typically seen at a median of 5-7 months. Multiple resistance mechanisms have been identified, including those that lead to reactivation of the MAPK pathway and other pathways, such as the PI3K-AKT-mTOR and VEGF pathways. Some patients with BRAF Val600 mutant melanoma seem to also benefit from immunotherapies such as high-dose interleukin 2 and ipilimumab, which, by contrast with BRAF inhibitors, can produce durable complete responses. We review the available data to best guide initial treatment choice and the sequence of treatments for patients with BRAF Val600 mutant melanoma.

    Topics: Antibodies, Monoclonal; Drug Resistance, Neoplasm; Humans; Imidazoles; Indoles; Ipilimumab; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2013

Trials

128 trial(s) available for pyrimidinones and trametinib

ArticleYear
Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2023, 05-10, Volume: 41, Issue:14

    No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (. In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic. Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily.. Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with

    Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Exanthema; GTP Phosphohydrolases; Humans; Lung Neoplasms; Melanoma; Membrane Proteins; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2023
Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial.
    Nature medicine, 2023, Volume: 29, Issue:5

    BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .

    Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Glioma; Humans; Imidazoles; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2023
A Phase II Redifferentiation Trial with Dabrafenib-Trametinib and 131I in Metastatic Radioactive Iodine Refractory BRAF p.V600E-Mutated Differentiated Thyroid Cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2023, 07-05, Volume: 29, Issue:13

    To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation.. A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq-150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months.. Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3-4 AEs in 7 patients.. Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.

    Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Humans; Iodine Radioisotopes; Mutation; Oximes; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Neoplasms; Thyrotropin Alfa

2023
Dabrafenib plus trametinib in patients with BRAF
    The Lancet. Oncology, 2022, Volume: 23, Issue:1

    Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAF. This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAF. Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).. Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAF. Novartis.

    Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Glioma; Humans; Imidazoles; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

2022
BAMM (BRAF Autophagy and MEK Inhibition in Melanoma): A Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine in Advanced BRAFV600-mutant Melanoma.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2022, 03-15, Volume: 28, Issue:6

    Autophagy is a resistance mechanism to BRAF/MEK inhibition in BRAFV600-mutant melanoma. Here we used hydroxychloroquine (HCQ) to inhibit autophagy in combination with dabrafenib 150 mg twice daily and trametinib 2 mg every day (D+T).. We conducted a phase I/II clinical trial in four centers of HCQ + D+T in patients with advanced BRAFV600-mutant melanoma. The primary objectives were the recommended phase II dose (RP2D) and the one-year progression-free survival (PFS) rate of >53%.. Thirty-four patients were evaluable for one-year PFS rate. Patient demographics were as follows: elevated lactate dehydrogenase: 47%; stage IV M1c/M1d: 52%; prior immunotherapy: 50%. In phase I, there was no dose-limiting toxicity. HCQ 600 mg orally twice daily with D+T was the RP2D. The one-year PFS rate was 48.2% [95% confidence interval (CI), 31.0%-65.5%], median PFS was 11.2 months (95% CI, 5.4-16.9 months), and response rate (RR) was 85% (95% CI, 64%-95%). The complete RR was 41% and median overall survival (OS) was 26.5 months. In a patient with elevated LDH (n = 16), the RR was 88% and median PFS and OS were 7.3 and 22 months, respectively.. HCQ + D+T was well tolerated and produced a high RR but did not meet criteria for success for the one-year PFS rate. There was a high proportion of patients with pretreated and elevated LDH, an increasingly common demographic in patients receiving targeted therapy. In this difficult-to-treat population, the RR and PFS were encouraging. A randomized trial of D+T + HCQ or placebo in patients with BRAFV600-mutant melanoma with elevated LDH and previous immunotherapy is being conducted.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Autophagy; Humans; Hydroxychloroquine; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2022
Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2022, Volume: 33, Issue:4

    Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up.. ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.. At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib.. These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

2022
Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2022, 05-01, Volume: 40, Issue:13

    Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with. Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic. At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03];. The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.

    Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Neoplasms, Second Primary; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Receptors, Death Domain; Skin Neoplasms

2022
Improved pyrexia-related outcomes associated with an adapted pyrexia adverse event management algorithm in patients treated with adjuvant dabrafenib plus trametinib: Primary results of COMBI-APlus.
    European journal of cancer (Oxford, England : 1990), 2022, Volume: 163

    COMBI-AD demonstrated long-term benefit of adjuvant dabrafenib plus trametinib in patients with resected stage III BRAF V600E/K-mutant melanoma; however, 9% of patients permanently discontinued therapy due to pyrexia. COMBI-APlus evaluated whether an adapted pyrexia management algorithm reduces high-grade pyrexia and pyrexia-related adverse outcomes.. COMBI-APlus is an open-label, phase IIIb trial evaluating an adapted pyrexia management algorithm in patients with high-risk resected stage III BRAF V600E/K-mutant melanoma treated with up to 12 months of adjuvant dabrafenib plus trametinib. Both drugs were interrupted for pyrexia (temperature ≥38°C) or the occurrence of pyrexia syndrome for suspected recurrent pyrexia. Treatment was restarted at the same dose once patients were symptom free for ≥24 h. The primary endpoint was the composite rate of grade 3/4 pyrexia, hospitalisation due to pyrexia, or permanent discontinuation due to pyrexia versus historical COMBI-AD control (20.0%; 95% confidence interval [CI], 16.3%-24.1%).. At data cutoff (5 October 2020), COMBI-APlus met its primary endpoint of significant improvement in the composite rate of pyrexia (8.0% [95% CI, 5.9%-10.6%]), with rates of 3.8% for grade 3/4 pyrexia, 4.3% for hospitalisation due to pyrexia, and 2.4% for discontinuation due to pyrexia. Estimated 12-month relapse-free survival was 91.8% (95% CI, 89.0%-93.9%). The most common adverse events were consistent with those in COMBI-AD, and 14.7% of patients permanently discontinued treatment due to adverse events.. The adapted pyrexia management algorithm appears to reduce the incidence of severe pyrexia outcomes, enables patients to manage pyrexia at home, and helps patients remain on treatment.. NCT03551626.

    Topics: Adjuvants, Immunologic; Algorithms; Antineoplastic Combined Chemotherapy Protocols; Fever; Humans; Imidazoles; Melanoma; Melanoma, Cutaneous Malignant; Mutation; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2022
Phase I pharmacokinetic study of single agent trametinib in patients with advanced cancer and hepatic dysfunction.
    Journal of experimental & clinical cancer research : CR, 2022, Feb-07, Volume: 41, Issue:1

    Trametinib is an oral MEK 1/2 inhibitor, with a single agent recommended phase 2 dose (RP2D) of 2 mg daily (QD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib in patients with advanced solid tumors who had various degrees of hepatic dysfunction (HD).. Advanced cancer patients were stratified into 4 HD groups based on Organ Dysfunction Working Group hepatic function stratification criteria: normal (Norm), mild (Mild), moderate (Mod), severe (Sev). Dose escalation was based on "3 + 3" design within each HD group. PK samples were collected at cycle 1 days 15-16.. Forty-six patients were enrolled with 44 evaluable for safety [Norm=17, Mild=7, Mod (1.5 mg)=4, Mod (2 mg)=5, Sev (1 mg)=9, Sev (1.5 mg)=2] and 22 for PK analysis. Treatment related adverse events were consistent with prior trametinib studies. No treatment related deaths occurred. Dose limiting toxicities (DLTs) were evaluable in 15 patients (Mild=6, Mod (1.5 mg)=3, Mod (2 mg)=2, Sev (1 mg)=3 and Sev (1.5 mg)=1). One DLT (grade 3 acneiform rash) was observed in a Sev patient (1.5 mg). Dose interruptions or reductions due to treatment related adverse events occurred in 15 patients (34%) [Norm=9, 53%; Mild=2, 29%; Mod (1.5 mg)=1, 33%; Mod (2 mg)=2, 33%; Sev (1 mg)=1, 11%; Sev (1.5 mg)=1; 50%]. There were no significant differences across HD groups for all PK parameters when trametinib was normalized to 2 mg. However, only limited PK data were available for the Mod (n = 3) and Sev (n = 3) groups compared to Norm (n = 10) and Mild (n = 6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p = 0.26).. RP2D for trametinib in Mild HD patients is 2 mg QD. There are insufficient number of evaluable patients due to difficulty of patient accrual to declare RP2D and MTD for Mod and Sev HD groups. DLTs were not observed in the highest dose cohorts that reached three evaluable patients - 1.5 mg QD in Mod group, and 1 mg QD in Sev group.. This study was registered in the ClinicalTrials.gov website ( NCT02070549 ) on February 25, 2014. .

    Topics: Adult; Aged; Female; Humans; Liver Diseases; Male; Middle Aged; Neoplasms; Pyridones; Pyrimidinones

2022
Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial.
    The Lancet. Oncology, 2022, Volume: 23, Issue:3

    There is paucity of investigations into immunotherapy or targeted therapy for postoperative locally recurrent pancreatic cancer. We aimed to assess the efficacy of stereotactic body radiotherapy (SBRT) plus pembrolizumab and trametinib in these patients.. In this open-label, randomised, controlled, phase 2 study, participants were recruited from Changhai Hospital affiliated to the Naval Medical University, Shanghai, China. Eligible patients were aged 18 years or older with histologically confirmed pancreatic ductal adenocarcinoma characterised by mutant KRAS and positive immunohistochemical staining of PD-L1, Eastern Cooperative Oncology Group performance status of 0 or 1, and documented local recurrence after surgery followed by chemotherapy (mFOLFIRINOX [ie, 5-fluorouracil, oxaliplatin, irinotecan, and folinic acid] or 5-fluorouracil). Eligible participants were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive SBRT with doses ranging from 35-40 Gy in five fractions, intravenous pembrolizumab 200 mg once every 3 weeks, and oral trametinib 2 mg once daily or SBRT (same regimen) and intravenous gemcitabine (1000 mg/m. Between Oct 10, 2016, and Oct 28, 2017, 198 patients were screened, of whom 170 patients were enrolled and randomly assigned to receive SBRT plus pembrolizumab and trametinib (n=85) or SBRT plus gemcitabine (n=85). As of the clinical cutoff date (Nov 30, 2020), median follow-up was 13·1 months (IQR 10·2-17·1). Median overall survival was 14·9 months (12·7-17·1) with SBRT plus pembrolizumab and trametinib and 12·8 months (95% CI 11·2-14·4) with SBRT plus gemcitabine (hazard ratio [HR] 0·69 [95% CI 0·51-0·95]; p=0·021). The most common grade 3 or 4 adverse effects were increased alanine aminotransferase or aspartate aminotransferase (ten [12%] of 85 in SBRT plus pembrolizumab and trametinib group vs six [7%] of 85 in SBRT plus gemcitabine group), increased blood bilirubin (four [5%] vs none), neutropenia (one [1%] vs nine [11%]), and thrombocytopenia (one [1%] vs four [5%]). Serious adverse events were reported by 19 (22%) participants in the SBRT plus pembrolizumab and trametinib group and 12 (14%) in the SBRT plus gemcitabine group. No treatment-related deaths occurred.. The combination of SBRT plus pembrolizumab and trametinib could be a novel treatment option for patients with locally recurrent pancreatic cancer after surgery. Phase 3 trials are needed to confirm our findings.. Shanghai Shenkang Center and Changhai Hospital.. For the Chinese translation of the abstract see Supplementary Materials section.

    Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; China; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Neoplasm Recurrence, Local; Pancreatic Neoplasms; Pyridones; Pyrimidinones; Radiosurgery

2022
Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases.
    Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2022, Volume: 170

    Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT.. Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1-3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint.. 10 patients were enrolled (median age-59 [47-64], BM-5 [1-10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3-4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion.. In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study.

    Topics: Brain; Brain Neoplasms; Cranial Irradiation; Humans; Middle Aged; Prospective Studies; Pyridones; Pyrimidinones; Radiosurgery

2022
A lead-in safety study followed by a phase 2 clinical trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600 mutant melanoma patients previously treated with BRAF-/MEK-inhibitors and immune checkpoint inhibitors.
    Melanoma research, 2022, 06-01, Volume: 32, Issue:3

    Patients with advanced BRAFV600 mutant melanoma who progressed on prior treatment with BRAF-/MEK-inhibitors and programmed cell death 1 or cytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitors can benefit from retreatment with the combination of a BRAF- and a MEK-inhibitor ('rechallenge'). Hydroxychloroquine can prevent autophagy-driven resistance and improve the efficacy of BRAF-/MEK-inhibitors in preclinical melanoma models. This clinical trial investigated the use of combined BRAF-/MEK-inhibition with dabrafenib and trametinib plus hydroxychloroquine in patients with advanced BRAFV600 mutant melanoma who previously progressed on prior treatment with BRAF-/MEK-inhibitors and immune checkpoint inhibitors. Following a safety lead-in phase, patients were randomized in the phase 2 part of the trial between upfront treatment with dabrafenib, trametinib and hydroxychloroquine (experimental arm), or dabrafenib and trametinib, with the possibility to add-on hydroxychloroquine at the time of documented tumor progression (contemporary control arm). Ten and four patients were recruited to the experimental and contemporary control arm, respectively. The objective response rate was 20.0% and the disease control rate was 50.0% in the experimental arm, whereas no responses were observed before or after adding hydroxychloroquine in the contemporary control arm. No new safety signals were observed for dabrafenib and trametinib. Hydroxychloroquine was suspected of causing an anxiety/psychotic disorder in one patient. Based on an early negative evaluation of the risk/benefit ratio for adding hydroxychloroquine to dabrafenib and trametinib when 'rechallenging' BRAFV600mutant melanoma patients, recruitment to the trial was closed prematurely.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Hydroxychloroquine; Imidazoles; Immune Checkpoint Inhibitors; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2022
A Phase II Study of Azacitidine, Venetoclax, and Trametinib in Relapsed or Refractory Acute Myeloid Leukemia Harboring RAS Pathway-Activating Mutations.
    Acta haematologica, 2022, Volume: 145, Issue:5

    RAS pathway mutations are common mechanisms of resistance to acute myeloid leukemia (AML) therapies. Trametinib, an oral MEK inhibitor, has been shown to have single-agent activity in relapsed/refractory AML and preclinical synergy with venetoclax.. We conducted a single-center, open-label, phase 2 trial of the combination of azacitidine, venetoclax, and trametinib in patients with relapsed or refractory AML harboring a RAS pathway-activating mutation.. Sixteen patients were treated. The patients were heavily pretreated with a median number of 4 prior therapies; 13 (81%) had received a prior hypomethylating agent (HMA) with venetoclax, and 8 (50%) had undergone prior stem cell transplant. Four patients (25%) responded (CR, n = 1; CRi, n = 1; MLFS, n = 2). Two of the 3 patients (67%) who had not previously received HMA plus venetoclax responded; in contrast, only 2 of the 13 patients (15%) who had previously received HMA plus venetoclax responded. The median OS was 2.4 months, and the 6-month OS rate was 31%. Related grade 3-4 adverse events occurred in 50% of patients, and 50% of patients required a dose adjustment of trametinib.. The combination of azacitidine, venetoclax, and trametinib had only modest activity in patients with relapsed/refractory AML, with a response rate that was similar to previous reports of trametinib monotherapy. Substantial toxicity was observed with this combination. Given the established role of RAS pathway mutations in mediating resistance to AML therapies, future studies of better tolerated, more active inhibitors of this pathway are still needed.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Mitogen-Activated Protein Kinase Kinases; Mutation; Pyridones; Pyrimidinones; Sulfonamides

2022
Comparative Bioavailability of a Single Dose of Trametinib (TMT212) Containing 9% vs 11% Dimethyl Sulfoxide in Randomized Healthy Volunteers to Assess Long-Term Storage at Room Temperature.
    Clinical pharmacology in drug development, 2022, Volume: 11, Issue:10

    Storage of trametinib tablets outside of 2-8°C protected from moisture may lead to loss of dimethyl sulfoxide (DMSO) and adversely impact trametinib bioavailability. In this open-label, phase 1, single-dose, randomized, 2-treatment, 2-period crossover study in healthy volunteers, bioavailability of a single 2-mg tablet of trametinib containing 9% DMSO (test formulation), corresponding to the lowest DMSO content in the tablet after storage at 25°C for 36 months, was evaluated vs bioavailability of a 2-mg tablet containing 11% DMSO (reference formulation). Sixty-five percent of subjects (n = 39/65) were men, and mean (standard deviation) age was 45.6 (11.17) years. Time to reach maximum plasma concentration occurred at 1.5 hours after dosing. The geometric mean ratio (90%CI) comparing 2-mg trametinib containing 9% DMSO with 2-mg trametinib containing 11% DMSO for area under the concentration-time curve from time 0 to the last measurable plasma concentration sampling time was 0.890 (0.848-0.935), suggesting the 2 formulations have similar bioavailability. The majority of adverse events were mild, with 1 subject experiencing 1 grade 3 headache. These results indicated that storage of trametinib at room temperatures ≤25°C during the overall shelf life of 36 months would not negatively impact trametinib bioavailability.

    Topics: Area Under Curve; Biological Availability; Cross-Over Studies; Dimethyl Sulfoxide; Female; Healthy Volunteers; Humans; Male; Middle Aged; Pyridones; Pyrimidinones; Tablets; Temperature; Therapeutic Equivalency

2022
A Phase I Clinical Trial of Trametinib in Combination with TAS-102 in Patients with Chemotherapy-Resistant RAS-Mutated (PIK3CA/PTEN-Wild Type) Metastatic Colorectal Cancer.
    Clinical colorectal cancer, 2022, Volume: 21, Issue:3

    We conducted a phase I study to evaluate the maximum tolerated dose (MTD), safety, and efficacy of trametinib in combination with TAS-102 in patients with chemotherapy-refractory KRAS-mutant, wild-type PIK3CA/PTEN metastatic colorectal cancer (mCRC).. A 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with chemorefractory mCRC without priorTAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m. 25 eligible patients were enrolled in this study. During the dose de-escalation phase, no dose-limiting toxicities (DLT) were observed at the full doses of trametinib/TAS-102 and the MTD was determined to be TAS-102 35 mg/m. Trametinib in combination with TAS-102 demonstrated a manageable safety profile. However, this combination did not achieve meaningful clinical benefit in patients with RAS-mutated PIK3CA and PTEN wild-type refractory mCRC.. NCT03317119.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; Drug Combinations; Humans; PTEN Phosphohydrolase; Pyridones; Pyrimidinones; Pyrrolidines; Thymine; Trifluridine

2022
Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC).
    Journal for immunotherapy of cancer, 2022, Volume: 10, Issue:8

    Monotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells.. Open-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4.. Twenty nine treated pts include 48% females, median age 48 years (range 28-75), and median prior therapies 2 (range 1-5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1-9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively).. T+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials.. NCT03428126.

    Topics: Adult; Aged; Antibodies, Monoclonal; Colorectal Neoplasms; Female; Hepatitis A Virus Cellular Receptor 2; Humans; Lung Neoplasms; Male; Microsatellite Repeats; Middle Aged; Programmed Cell Death 1 Receptor; Pyridones; Pyrimidinones; Tumor Microenvironment

2022
An open label, non-randomised, phase IIIb study of trametinib in combination with dabrafenib in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: A subgroup analysis of patients with brain metastases.
    European journal of cancer (Oxford, England : 1990), 2022, Volume: 175

    Despite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T).. This phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at p < 0.05.. Between March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval [CI], 5.29-6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors.. This is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOG >1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Imidazoles; Lactate Dehydrogenases; Male; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2022
Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis.
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2022, Volume: 17, Issue:1

    Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data.. Pretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety.. At data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5-78.5) and 16.3 (range: 0.4-80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8-80.1) and 63.9% (46.2-79.2), median progression-free survival (95% CI) was 10.2 (6.9-16.7) and 10.8 (7.0-14.5) months, and median overall survival (95% CI) was 18.2 (14.3-28.6) and 17.3 (12.3-40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation.. Dabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Genomics; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

2022
Uveitis associated with cancer immunotherapy: long-term outcomes.
    Immunotherapy, 2021, Volume: 13, Issue:18

    Lay abstract This study aims to report the long-term outcome of intra-ocular inflammation (uveitis) associated with cancer immunotherapy (CIT). Serial patients complaining of blurred vision and painful eyes showed intra-ocular inflammation that was related to CIT, after infectious, inflammatory and tumoral causes of uveitis have been ruled out. The length of follow-up was more than 12 months for most patients. Eight serial patients treated with rituximab (anti-CD20), nivolumab (anti-PD-1), ipilimumab (anti-CTLA-4), vemurafenib and dabrafenib (anti-BRAF), trametinib (anti-MEK) and ibritunib showed intra-ocular inflammation with hypopion (one patient), macular edema (five patients) and choroiditis (two patients). Various regimens of corticosteroid therapy showed a favorable ophthalmological outcome, whether the CIT was continuing or suspended. Local corticosteroid injections in combination with CIT could be suggested as a first-line treatment. This could help to preserve the quality of life without threatening the vital prognosis.

    Topics: Adrenal Cortex Hormones; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Immunotherapy; Ipilimumab; Male; Middle Aged; Neoplasms; Nivolumab; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Rituximab; Uveitis; Vemurafenib

2021
Intermittent BRAF inhibition in advanced BRAF mutated melanoma results of a phase II randomized trial.
    Nature communications, 2021, 12-01, Volume: 12, Issue:1

    Combination treatment with BRAF (BRAFi) plus MEK inhibitors (MEKi) has demonstrated survival benefit in patients with advanced melanoma harboring activating BRAF mutations. Previous preclinical studies suggested that an intermittent dosing of these drugs could delay the emergence of resistance. Contrary to expectations, the first published phase 2 randomized study comparing continuous versus intermittent schedule of dabrafenib (BRAFi) plus trametinib (MEKi) demonstrated a detrimental effect of the "on-off" schedule. Here we report confirmatory data from the Phase II randomized open-label clinical trial comparing the antitumoral activity of the standard schedule versus an intermittent combination of vemurafenib (BRAFi) plus cobimetinib (MEKi) in advanced BRAF mutant melanoma patients (NCT02583516). The trial did not meet its primary endpoint of progression free survival (PFS) improvement. Our results show that the antitumor activity of the experimental intermittent schedule of vemurafenib plus cobimetinib is not superior to the standard continuous schedule. Detection of BRAF mutation in cell free tumor DNA has prognostic value for survival and its dynamics has an excellent correlation with clinical response, but not with progression. NGS analysis demonstrated de novo mutations in resistant cases.

    Topics: Aged; Antineoplastic Agents; Azetidines; Humans; Imidazoles; Melanoma; Mutation; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

2021
Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2021, 04-15, Volume: 27, Issue:8

    In a head and neck squamous cell carcinoma (HNSCC) "window of opportunity" clinical trial, we reported that trametinib reduced MEK-Erk1/2 activation and resulted in tumor responses in a subset of patients. Here, we investigated resistance to trametinib and molecular correlates in HNSCC cell lines and patient samples.. HNSCC cell lines were treated with trametinib to generate resistant lines. Candidate bypass pathways were assessed using immunoblotting, CRISPR knockout, and survival assays. Effectiveness of combined trametinib and verteporfin targeting was evaluated. Patient-derived xenografts (PDXs) from responder patients were treated with trametinib and resistant tumors were analyzed. Window trial clinical samples were subjected to whole-exome and RNA sequencing.. HNSCC cell lines developed resistance (CAL27-TR and HSC3-TR) after prolonged trametinib exposure. Downstream effectors of the Hippo pathway were activated in CAL27-TR and HSC3-TR, and combined trametinib and verteporfin treatment resulted in synergistic treatment response. We defined the Hippo pathway effector Yap1 as an induced survival pathway promoting resistance to trametinib in HSC3-TR. Yap1 was necessary for HSC3-TR trametinib resistance, and constitutively active Yap1 was sufficient to confer resistance in parental HSC3. Analysis of trametinib neoadjuvant trial patient tumors indicated canonical MEK-Erk1/2 pathway activating mutations were infrequent, and Yap1 activity increased following trametinib treatment. Trametinib treatment of a PDX from a responder patient resulted in evolution of resistance with increased Yap1 expression and activity.. These studies identify a Yap1-dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response.

    Topics: Animals; Biopsy; Cell Line, Tumor; Drug Resistance, Neoplasm; Exome Sequencing; Female; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Head and Neck Neoplasms; Hippo Signaling Pathway; Humans; MAP Kinase Signaling System; Mice; Pyridones; Pyrimidinones; RNA-Seq; Squamous Cell Carcinoma of Head and Neck; Xenograft Model Antitumor Assays; YAP-Signaling Proteins

2021
Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study.
    The Lancet. Oncology, 2021, Volume: 22, Issue:3

    Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Cell-free circulating tumour DNA (ctDNA) is a promising biomarker; however, various detection methods have been used, and, to date, no large studies have examined the association between serial changes in ctDNA and survival after BRAF, MEK, or BRAF plus MEK inhibitor therapy. We aimed to evaluate whether baseline ctDNA concentrations and kinetics could predict survival outcomes.. In this clinical validation study, we used analytically validated droplet digital PCR assays to measure BRAF. In COMBI-d, pretreatment plasma samples were available from 345 (82%) of 423 patients and on-treatment (week 4) plasma samples were available from 224 (53%) of 423 patients. In cohort A of COMBI-MB, pretreatment and on-treatment samples were available from 38 (50%) of 76 patients with intracranial and extracranial metastatic melanoma. ctDNA was detected in pretreatment samples from 320 (93%) of 345 patients (COMBI-d) and 34 (89%) of 38 patients (COMBI-MB). When assessed as a continuous variable, elevated baseline BRAF. Pretreatment and on-treatment BRAF. Novartis.

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Circulating Tumor DNA; Double-Blind Method; Female; Follow-Up Studies; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Prognosis; Pyridones; Pyrimidinones; Survival Rate

2021
Neoadjuvant Cytoreductive Treatment With BRAF/MEK Inhibition of Prior Unresectable Regionally Advanced Melanoma to Allow Complete Surgical Resection, REDUCTOR: A Prospective, Single-arm, Open-label Phase II Trial.
    Annals of surgery, 2021, 08-01, Volume: 274, Issue:2

    To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma.. Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear.. In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8 weeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection.. Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50 months (interquartile range 37.7-57.1 months), median recurrence-free survival was 9.9 months (95% confidence interval 7.52-not reached) in patients undergoing surgery.. This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cytoreduction Surgical Procedures; Female; Humans; Imidazoles; Magnetic Resonance Imaging; Male; Melanoma; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Netherlands; Oximes; Positron Emission Tomography Computed Tomography; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
Efficacy and Safety of Trametinib in Non-V600 BRAF Mutant Melanoma: A Phase II Study.
    The oncologist, 2021, Volume: 26, Issue:9

    This study suggests that trametinib has significant clinical activity in non-V600 BRAF mutation and BRAF fusion metastatic melanoma, albeit in a small cohort. All patients with metastatic melanoma should undergo sequencing of the BRAF gene to identify noncanonical BRAF mutations that may indicate benefit from treatment with trametinib.. Non-V600 BRAF mutations and BRAF fusions in aggregate occur in approximately 5% of all melanomas. Inhibition of the mitogen-activated protein kinase (MAPK) pathway has been implicated as a possible treatment strategy for these patients.. In this open-label, multicenter, phase II study, patients with advanced melanoma harboring mutations in BRAF outside V600 (non-V600) or BRAF fusions received trametinib 2.0 mg daily. Patients were divided into cohorts based on the intrinsic catalytic activity of BRAF mutation (high, cohort A; low/unknown, cohort B). The primary endpoint was objective response rate (ORR) for patients in cohort A; secondary endpoints included ORR in cohort B, safety, and survival in both treatment arms.. Among all patients, the ORR was 33% (three of nine patients), including 67% in cohort A and 17% in cohort B. Two patients had stable disease as best response, and six patients had some degree of tumor shrinkage. The median progression-free survival (PFS) was 7.3 months. Treatment-related adverse events occurred in all patients (100%); most (89%) were grade 1-2.. In contrast to recently described tumor-agnostic studies in a genetically similar population, trametinib had considerable activity in a small population of patients with melanoma harboring BRAF non-V600 mutations and fusions, providing rationale for sequencing in search of these genomic alterations.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2021
Molecular Profiling-Based Assignment of Cancer Therapy (NCI-MPACT): A Randomized Multicenter Phase II Trial.
    JCO precision oncology, 2021, Volume: 5

    This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm).. Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway.. Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%;. Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzimidazoles; Carboplatin; DNA, Neoplasm; Double-Blind Method; Everolimus; Female; Gene Expression Profiling; Humans; Male; Middle Aged; Molecular Diagnostic Techniques; Neoplasms; Pyrazoles; Pyridones; Pyrimidinones; Temozolomide; Young Adult

2021
Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial.
    The Lancet. Oncology, 2021, Volume: 22, Issue:8

    There is paucity of investigations into immunotherapy or targeted therapy for postoperative locally recurrent pancreatic cancer. We aimed to assess the efficacy of stereotactic body radiotherapy (SBRT) plus pembrolizumab and trametinib in these patients.. In this open-label, randomised, controlled, phase 2 study, participants were recruited from Changhai Hospital affiliated to Naval Medical University, Shanghai, China. Eligible patients were aged 18 years or older with histologically confirmed pancreatic ductal adenocarcinoma characterised by mutant KRAS and positive immunohistochemical staining of PD-L1, Eastern Cooperative Oncology Group performance status of 0 or 1, and documented local recurrence after surgery followed by chemotherapy (mFOLFIRINOX or 5-fluorouracil). Eligible participants were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive SBRT with doses ranging from 35-40 Gy in five fractions, intravenous pembrolizumab 200 mg once every 3 weeks, and oral trametinib 2 mg once daily or SBRT (same regimen) and intravenous gemcitabine (1000 mg/m. Between Oct 10, 2016, and Oct 28, 2017, 198 patients were screen, of whom 170 patients were enrolled and randomly assigned to receive SBRT plus pembrolizumab and trametinib (n=85) or SBRT plus gemcitabine (n=85). As of the clinical cutoff date (Nov 30, 2020), median follow-up was 23·3 months (IQR 20·5-27·4). Median overall survival was 24·9 months (23·3-26·5) with SBRT plus pembrolizumab and trametinib and 22·4 months (95% CI 21·2-23·6) with SBRT plus gemcitabine (hazard ratio [HR] 0·60 [95% CI 0·44-0·82]; p=0·0012). The most common grade 3 or 4 adverse effects were increased alanine aminotransferase or aspartate aminotransferase (ten [12%] of 85 in SBRT plus pembrolizumab and trametinib group vs six [7%] of 85 in SBRT plus gemcitabine group), increased blood bilirubin (four [5%] vs none), neutropenia (one [1%] vs nine [11%]), and thrombocytopenia (one [1%] vs four [5%]). Serious adverse events were reported by 19 (22%) participants in the SBRT plus pembrolizumab and trametinib group and 12 (14%) in the SBRT plus gemcitabine group. No treatment-related deaths occurred.. The combination of SBRT plus pembrolizumab and trametinib could be a novel treatment option for patients with locally recurrent pancreatic cancer after surgery. Phase 3 trials are needed to confirm our findings.. Shanghai Shenkang Center and Changhai Hospital.. For the Chinese translation of the abstract see Supplementary Materials section.

    Topics: Aged; Antibodies, Monoclonal, Humanized; Carcinoma, Pancreatic Ductal; China; Combined Modality Therapy; Deoxycytidine; Female; Gemcitabine; Humans; Male; Middle Aged; Pancreatic Neoplasms; Pyridones; Pyrimidinones; Radiosurgery

2021
Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabraf
    European journal of cancer (Oxford, England : 1990), 2021, Volume: 154

    BRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups.. Patients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan-Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis.. Between March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33-8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with <3 metastatic sites, ECOG = 0 and no BM had the highest probability of PFS at 6 months (83%, 95% CI 76-87) and 12 months (56%, 95% CI 47-64), respectively.. This is the largest prospective study in advanced BRAF V600-mutant melanoma patients treated with D + T, conducted in conditions close to 'real-world practice'. We confirm previous findings that LDH, ECOG PS and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Oximes; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
Phase II Trial of Trametinib and Panitumumab in RAS/RAF Wild Type Metastatic Colorectal Cancer.
    Clinical colorectal cancer, 2021, Volume: 20, Issue:4

    MEK inhibition may overcome resistance to EGFR inhibition in patients with RAS wildtype (wt) metastatic colorectal cancer (mCRC). We evaluated antitumor activity of trametinib (MEK1/2 inhibitor) with panitumumab (EGFR monoclonal antibody) in a phase II trial.. Patients with KRAS, NRAS, and BRAF wt mCRC with prior 5-FU, irinotecan, oxaliplatin, +/- bevacizumab and no prior anti-EGFR therapy were treated with trametinib 1.5 mg oral daily and panitumumab 4.8 mg/kg IV every 2 weeks. Primary endpoint was clinical benefit rate (CB; CR, PR, or SD ≥24 weeks) by RECIST v1.1. A 2-stage minimax design was used. Serial plasma circulating free DNA (cfDNA) was collected and profiled using Oncomine Lung cfDNA assay.. Fourteen patients were enrolled from November 2015 to April 2019. CB rate was 38% (5/13) and median progression free survival (PFS) was 4.4 months (95% CI, 2.9-7.1). Confirmed overall response rate was 38% (5/13). Treatment-related AE (trAE) included acneiform rash (85%), diarrhea (62%), maculopapular rash (54%), mucositis (46%), and others. Dose modifications and interruptions of trametinib occurred in 69% and panitumumab in 54% of patients. The trial did not progress to stage II accrual due to tolerability and short duration of response. RAS or BRAF mutations cfDNA were detected in 3/13 patients (23%) before radiographic disease progression.. The addition of trametinib to panitumumab led to a high rate of tumor shrinkage in RAS/RAF wt metastatic colorectal cancer, with poor tolerability due to a high incidence of skin toxicity. Median PFS was similar to panitumumab alone in historical control data.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Panitumumab; Pyridones; Pyrimidinones

2021
Validation of dabrafenib-trametinib prognostic groups in patients treated with vemurafenib and cobimetinib for advanced BRAF-mutated melanoma.
    Melanoma research, 2020, Volume: 30, Issue:3

    Prognostic groups defined by lactate dehydrogenase concentration and number of organ sites containing metastases have been reported for patients treated with dabrafenib and trametinib for advanced melanoma. We aimed to validate these prognostic groups for patients treated with vemurafenib and cobimetinib in the coBRIM and BRIM-3 clinical studies. Eight hundred nine patients were included, 240 treated with vemurafenib plus cobimetinib and 569 with vemurafenib. For patients treated with vemurafenib and cobimetinib, both overall survival (P < 0.001, c-statistic = 0.72) and progression-free survival (P < 0.001, c-statistic = 0.65) differed markedly between prognostic groups. Two-year progression-free survival ranged from 3 (lactate dehydrogenase ≥2 times the upper limit of normal) to 50% (normal lactate dehydrogenase and ≤3 sites), and two-year overall survival ranged from 7 to 71%. For patients treated with vemurafenib monotherapy, overall survival (P < 0.001, c-statistic = 0.66) and progression-free survival (P < 0.001, c-statistic = 0.62) also differed significantly between prognostic groups. In conclusion, prognostic groups identified for patients treated with dabrafenib and trametinib are also applicable to patients treated with vemurafenib and cobimentinib.

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biomarkers; Female; Humans; Imidazoles; L-Lactate Dehydrogenase; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Mutation; Oximes; Piperidines; Prognosis; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Vemurafenib

2020
Trametinib Activity in Patients with Solid Tumors and Lymphomas Harboring BRAF Non-V600 Mutations or Fusions: Results from NCI-MATCH (EAY131).
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 04-15, Volume: 26, Issue:8

    Substantial preclinical evidence and case reports suggest that MEK inhibition is an active approach in tumors with. The NCI-MATCH study performed genomic profiling on tumor samples from patients with solid tumors and lymphomas progressing on standard therapies or with no standard treatments. Patients with prespecified fusions and non-V600 mutations in. Among 50 patients assigned, 32 were eligible and received therapy with trametinib. Of these, 1 had a. Trametinib did not show promising clinical activity in patients with tumors harboring non-V600

    Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Lymphoma; Male; Middle Aged; Mutation; National Cancer Institute (U.S.); Neoplasms; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate; Treatment Outcome; United States

2020
Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAF
    The Lancet. Oncology, 2020, Volume: 21, Issue:3

    Adjuvant dabrafenib plus trametinib reduced the risk of relapse versus placebo in patients with resected, BRAF. COMBI-AD is a randomised, double-blind, placebo-controlled, phase 3 trial comparing dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily versus two matched placebos. Study participants were at least 18 years of age and underwent complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma, per American Joint Committee on Cancer 7th edition criteria, with a BRAF. Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled in the trial. Median follow-up at data cutoff (April 30, 2018) was 44 months (IQR 38-49) in the dabrafenib plus trametinib group and 42 months (21-49) in the placebo group. Intrinsic tumour genomic features were assessed in 368 patients (DNA sequencing set) and tumour microenvironment characteristics were assessed in 507 patients (NanoString biomarker set). MAPK pathway genomic alterations at baseline did not affect treatment benefit or clinical outcome. An IFNγ gene expression signature higher than the median was prognostic for prolonged relapse-free survival in both treatment groups. Tumour mutational burden was independently prognostic for relapse-free survival in the placebo group (high TMB, top third; hazard ratio [HR] 0·56, 95% CI 0·37-0·85, p=0·0056), but not in the dabrafenib plus trametinib group (0·83, 95% CI 0·53-1·32, p=0·44). Patients with tumour mutational burden in the lower two terciles seem to derive a substantial long-term relapse-free survival benefit from targeted therapy (HR [versus placebo] 0·49, 95% CI 0·35-0·68, p<0·0001). However, patients with high tumour mutational burden seem to have a less pronounced benefit with targeted therapy (HR [versus placebo] 0·75, 95% CI 0·44-1·26, p=0·27), especially if they had an IFNγ signature lower than the median (HR 0·88 [95% CI 0·40-1·93], p=0·74).. Tumour mutational burden alone or in combination with IFNγ gene expression signature or other markers for an adaptive immune response might be of relevance for identifying patients with stage III melanoma who might derive clinical benefit from targeted therapy. Further validation in prospective clinical trials is warranted.. Novartis Pharmaceuticals.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Recurrence, Local; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Salvage Therapy; Skin Neoplasms; Survival Rate; Young Adult

2020
Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors.
    Cancer chemotherapy and pharmacology, 2020, Volume: 85, Issue:4

    This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition.. This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD.. Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses).. Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Diamines; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Maximum Tolerated Dose; Melanoma; Middle Aged; Prognosis; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridones; Pyrimidinones; Tissue Distribution; Triple Negative Breast Neoplasms; Young Adult

2020
Randomised phase II trial (SWOG S1310) of single agent MEK inhibitor trametinib Versus 5-fluorouracil or capecitabine in refractory advanced biliary cancer.
    European journal of cancer (Oxford, England : 1990), 2020, Volume: 130

    The rationale for the evaluation of trametinib in advanced biliary cancer (BC) is based on the presence of mitogen-activated protein kinase alterations and on earlier promising results with MEK inhibitors in BC.. Patients with histologically proven BC who progressed on gemcitabine/platinum were randomised to trametinib daily (arm 1) versus fluoropyrimidine therapy (infusional 5-fluorouracil or oral capecitabine, arm 2). The primary end-point was overall survival (OS). Secondary end-points included progression free survival (PFS) and response rate. A planned interim futility analysis of objective response was performed on the first 14 patients registered to the trametinib arm.. The study was stopped early based on the lack of measurable response in the trametinib arm. A total of 44 eligible patients were randomised (24 patients in arm 1 and 20 patients in arm 2). Median age was 62 years and the primary sites of tumour were cholangiocarcinoma (68%) and gallbladder (32%). The overall response rate was 8% (95% CI 0%-19%) in arm 1 versus 10% (95% CI 0%-23%) in arm 2 (p > .99) Median OS was 4.3 months for arm 1 and 6.6 months for arm 2. The median PFS was 1.4 months for arm 1 and 3.3 months for arm 2.. This is the first prospective randomised study of a targeted agent versus chemotherapy for the second-line treatment of BC. In this unselected population, the interim analysis result of unlikely benefit with trametinib resulted in early closure.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Capecitabine; Female; Fluorouracil; Humans; Male; Middle Aged; Pyridones; Pyrimidinones

2020
Phase I Trial of Trametinib with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 07-01, Volume: 26, Issue:13

    Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses.. The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a

    Topics: Aged; Biomarkers, Tumor; Chemoradiotherapy; Combined Modality Therapy; Disease Management; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Rectal Neoplasms; Treatment Outcome

2020
Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer.
    Cancer chemotherapy and pharmacology, 2020, Volume: 85, Issue:5

    KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R).. Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively.. Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected.. Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Lapatinib; Male; Middle Aged; Mutation; Pancreatic Neoplasms; Pharmacogenetics; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Treatment Outcome

2020
Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience.
    Journal of pediatric hematology/oncology, 2020, Volume: 42, Issue:8

    MEK inhibitors are an emerging therapy with increasing use in mitogen-activated protein kinase-driven central nervous system (CNS) tumors. There is limited data regarding efficacy and toxicity in pediatric patients. We report our clinical experience with trametinib-based therapy for the treatment of 14 consecutive pediatric patients with recurrent low-grade glioma (N=11) or high-grade CNS tumors (N=3) with MAP kinase pathway mutations. Patients received trametinib as monotherapy (N=9) or in combination (N=5) with another antineoplastic agent. Nine patients (64%) were progression free during treatment. Five patients showed a partial response, while 4 had stable disease. Two patients (14%) progressed on therapy. All partial responses were in patients with low-grade tumors. The remaining 3 patients were not evaluable due to toxicity limiting duration of therapy. Two of 3 patients with low-grade glioma with leptomeningeal dissemination showed radiographic treatment response. Five patients reported improved clinical symptoms while on trametinib. Adverse events on trametinib-based therapy included dermatologic, mouth sores, fever, gastrointestinal, infection, neutropenia, headache, and fatigue, and were more common in patients using combination therapy. Trametinib-based therapy demonstrated signals of efficacy in our single institutional cohort of pediatric patients with mitogen-activated protein kinase-driven CNS tumors. Our observations need to be confirmed in a clinical trial setting.

    Topics: Adolescent; Antineoplastic Agents; Central Nervous System Neoplasms; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Male; Prognosis; Pyridones; Pyrimidinones; Retrospective Studies

2020
Open-label, phase IIa study of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma.
    European journal of cancer (Oxford, England : 1990), 2020, Volume: 135

    This study (NCT02083354) assessed the efficacy and safety of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma.. Overall, 77 patients of East Asian origin (including 61 from Mainland China) with unresectable or metastatic BRAF V600-mutant cutaneous melanoma were enrolled. Prior treatment was allowed except with BRAF/MEK inhibitors. Patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end-point was objective response rate (ORR) using Response Evaluation Criteria in Solid Tumours 1.1. Secondary end-points were duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetics and safety.. These results support the efficacy and tolerability of dabrafenib in combination with trametinib in East Asian patients with unresectable or metastatic BRAF V600-mutant cutaneous melanoma.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asia; Biomarkers, Tumor; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Oximes; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Time Factors

2020
A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer.
    The oncologist, 2020, Volume: 25, Issue:12

    The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy. Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily. The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.. The RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.. This was a phase I study with a 3+3 design in patients with treatment-naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.. A total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose-limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment-related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression-free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated-ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated-ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.. Trametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Humans; Leukocytes, Mononuclear; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Pyridones; Pyrimidinones; Sorafenib

2020
Dabrafenib plus trametinib in patients with BRAF
    The Lancet. Oncology, 2020, Volume: 21, Issue:9

    Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAF. This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAF. Between March 12, 2014, and July 18, 2018, 43 patients with BRAF. Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAF. GlaxoSmithKline and Novartis.

    Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Disease-Free Survival; Female; Humans; Imidazoles; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

2020
Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma.
    The New England journal of medicine, 2020, 09-17, Volume: 383, Issue:12

    In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with. We randomly assigned 870 patients who had resected stage III melanoma with. The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period.. In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with

    Topics: Adjuvants, Immunologic; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Double-Blind Method; Female; Follow-Up Studies; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Analysis

2020
Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial.
    Nature medicine, 2020, Volume: 26, Issue:10

    Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAF

    Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation, Missense; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Analysis; Treatment Outcome; Young Adult

2020
Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i.
    Nature medicine, 2020, Volume: 26, Issue:10

    Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cohort Studies; Disease Progression; Female; Humans; Imidazoles; Immune Checkpoint Inhibitors; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation, Missense; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Young Adult

2020
PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma.
    Nature communications, 2020, 12-07, Volume: 11, Issue:1

    Combining PD-L1 blockade with inhibition of oncogenic mitogen-activated protein kinase (MAPK) signaling may result in long-lasting responses in patients with advanced melanoma. This phase 1, open-label, dose-escalation and -expansion study (NCT02027961) investigated safety, tolerability and preliminary efficacy of durvalumab (anti-PD-L1) combined with dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) for patients with BRAF-mutated melanoma (cohort A, n = 26), or durvalumab and trametinib given concomitantly (cohort B, n = 20) or sequentially (cohort C, n = 22) for patients with BRAF-wild type melanoma. Adverse events and treatment discontinuation rates were more common than previously reported for these agents given as monotherapy. Objective responses were observed in 69.2% (cohort A), 20.0% (cohort B) and 31.8% (cohort C) of patients, with evidence of improved tumor immune infiltration and durable responses in a subset of patients with available biopsy samples. In conclusion, combined MAPK inhibition and anti-PD-L1 therapy may provide treatment options for patients with advanced melanoma.

    Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Cohort Studies; Diarrhea; Exanthema; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Oximes; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Young Adult

2020
KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in
    Journal for immunotherapy of cancer, 2020, Volume: 8, Issue:2

    In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported.. The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated. Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3-5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet.. In

    Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Female; Humans; Imidazoles; Male; Melanoma; Oximes; Pyridones; Pyrimidinones; Survival Analysis

2020
Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer: An NRG Oncology/GOG study.
    Gynecologic oncology, 2019, Volume: 155, Issue:3

    We sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer.. Patients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1).. Of 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant. Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity. There were no responses in DL1 (0%, 90%CI 0-15%) and 1 response in DL-1 (8.3%, 90%CI 0.4-33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1.. The combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Diamines; Endometrial Neoplasms; Female; Humans; MAP Kinase Kinase Kinases; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridones; Pyrimidinones

2019
A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01.
    BMC cancer, 2019, Dec-27, Volume: 19, Issue:1

    Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study.. The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment.. Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN.. ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

    Topics: Adolescent; Antineoplastic Agents; Canada; Child; Child, Preschool; Glioma; Humans; Infant; MAP Kinase Signaling System; Neurofibroma, Plexiform; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Treatment Outcome; Young Adult

2019
FREQUENT SUBCLINICAL MACULAR CHANGES IN COMBINED BRAF/MEK INHIBITION WITH HIGH-DOSE HYDROXYCHLOROQUINE AS TREATMENT FOR ADVANCED METASTATIC BRAF MUTANT MELANOMA: Preliminary Results From a Phase I/II Clinical Treatment Trial.
    Retina (Philadelphia, Pa.), 2019, Volume: 39, Issue:3

    To assess the potential ocular toxicity of a combined BRAF inhibition (BRAFi) + MEK inhibition (MEKi) + hydroxychloroquine (HCQ) regime used to treat metastatic BRAF mutant melanoma.. Patients with stage IV metastatic melanoma and BRAF V600E mutations (n = 11, 31-68 years of age) were included. Treatment was with oral dabrafenib, 150 mg bid, trametinib, 2 mg/day, and HCQ, 400 mg to 600 mg bid. An ophthalmic examination, spectral domain optical coherence tomography, near-infrared and short-wavelength fundus autofluorescence, and static perimetry were performed at baseline, 1 month, and q/6 months after treatment.. There were no clinically significant ocular events; there was no ocular inflammation. The only medication-related change was a separation of the photoreceptor outer segment tip from the apical retinal pigment epithelium that could be traced from the fovea to the perifoveal retina noted in 9/11 (82%) of the patients. There were no changes in retinal pigment epithelium melanization or lipofuscin content by near-infrared fundus autofluorescence and short-wavelength fundus autofluorescence, respectively. There were no inner retinal or outer nuclear layer changes. Visual acuities and sensitivities were unchanged.. BRAFi (trametinib) + MEKi (dabrafenib) + HCQ causes very frequent, subclinical separation of the photoreceptor outer segment from the apical retinal pigment epithelium without inner retinal changes or signs of inflammation. The changes suggest interference with the maintenance of the outer retinal barrier and/or phagocytic/pump functions of the retinal pigment epithelium by effective MEK inhibition.

    Topics: Adult; Aged; Antineoplastic Agents; Enzyme Inhibitors; Female; Humans; Hydroxychloroquine; Imidazoles; Macula Lutea; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Oximes; Photoreceptor Cells; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Diseases; Retinal Pigment Epithelium

2019
Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2019, 02-01, Volume: 30, Issue:2

    Advanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF (BRAF-wt) melanoma. However, the mitogen-activated protein kinase pathway is activated in most melanoma, including BRAF-wt. We assessed whether inhibiting this pathway by adding kinase inhibitors trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF-wt melanoma in a phase II, randomised and open-label trial.. Patients were randomised (1 : 1 : 1) to paclitaxel alone or with trametinib or pazopanib. Paclitaxel was given for a maximum of six cycles, while 2 mg trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS) and objective response rate (ORR).. Participants were randomised to paclitaxel alone (n = 38), paclitaxel and trametinib (n = 36), or paclitaxel and pazopanib (n = 37). Adding trametinib significantly improved 6-month PFS [time ratio (TR), 1.47; 90% confidence interval (CI) 1.08-2.01, P = 0.04] and ORR (42% versus 13%; P = 0.01) but had no effect on OS (P = 0.25). Adding pazopanib did not benefit 6-month PFS; (TR 1.36; 90% CI 0.96-1.93; P = 0.14), ORR, or OS. Toxicity increased in both combination arms.. In this phase II trial, adding trametinib to paclitaxel chemotherapy for BRAF-wt melanoma improved PFS and substantially increased ORR but did not impact OS.This study was registered with the EU Clinical Trials Register, EudraCT number 2011-002545-35, and with the ISRCTN registry, number 43327231.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Indazoles; Male; Melanoma; Middle Aged; Mutation; Paclitaxel; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones; Sulfonamides; Survival Rate

2019
Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.
    Nature communications, 2019, 01-16, Volume: 10, Issue:1

    FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.

    Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Epigenesis, Genetic; Exome Sequencing; Female; fms-Like Tyrosine Kinase 3; GTP Phosphohydrolases; HEK293 Cells; Humans; Inhibitory Concentration 50; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Male; Membrane Proteins; Mice; Middle Aged; Mutation; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Tandem Repeat Sequences; Treatment Outcome

2019
Pharmacokinetic and cytokine profiles of melanoma patients with dabrafenib and trametinib-induced pyrexia.
    Cancer chemotherapy and pharmacology, 2019, Volume: 83, Issue:4

    The combination of a BRAF inhibitor dabrafenib and a MEK inhibitor trametinib (CombiDT) has improved outcomes compared with chemotherapy or BRAF inhibitor monotherapy in advanced BRAF V600E/K melanoma. However, CombiDT causes a high incidence of pyrexia and treatment interruptions. Pharmacokinetic analysis may provide an explanation for the pyrexia.. 34 patients with Stage 3 BRAF V600 melanoma were treated with CombiDT on a clinical trial between August 2014 and June 2017. Plasma concentrations of drugs and metabolites were determined using validated LC-MS assays, in addition to analysis of a panel of cytokines.. No apparent associations between pyrexia and exposure to the drugs or metabolites could be observed. Greater elevations in IL-1B and IL-6 were observed in patients with pyrexia during the first week of treatment compared to those without pyrexia.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chromatography, Liquid; Cytokines; Drug Combinations; Female; Fever; Humans; Imidazoles; Interleukin-1beta; Interleukin-6; Male; Mass Spectrometry; Melanoma; Middle Aged; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

2019
Targeted agents or immuno-oncology therapies as first-line therapy for BRAF-mutated metastatic melanoma: a real-world study.
    Future oncology (London, England), 2019, Sep-01, Volume: 15, Issue:25

    Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; CTLA-4 Antigen; Disease-Free Survival; Female; Humans; Imidazoles; Immunotherapy; Ipilimumab; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Nivolumab; Oximes; Piperidines; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome; Vemurafenib

2019
Comparative efficacy of combination immunotherapy and targeted therapy in the treatment of BRAF-mutant advanced melanoma: a matching-adjusted indirect comparison.
    Immunotherapy, 2019, Volume: 11, Issue:7

    Comparison of clinical outcomes of nivolumab + ipilimumab versus BRAF + MEK inhibitors (dabrafenib + trametinib or vemurafenib + cobimetinib) in BRAF-mutant advanced melanoma.. Matching-adjusted indirect comparisons were conducted between nivolumab + ipilimumab (CheckMate 067/069 studies) and BRAF + MEK inhibitors (COMBI-d, COMBI-v and coBRIM studies). Overall survival (OS), progression-free survival and objective response rates were assessed.. After adjusting, nivolumab + ipilimumab showed improved OS versus dabrafenib + trametinib (hazard ratio [HR] = 0.64; 95% CI: 0.46-0.89) or vemurafenib + cobimetinib (HR = 0.56; 95% CI: 0.36-0.89); OS outcomes were similar at 1 year, with benefits emerging after 12 months; progression-free survival and objective response rates were similar. Grade 3/4 adverse events occurred in 54.1% with nivolumab + ipilimumab, 31.6% with dabrafenib + trametinib and 59.5% with vemurafenib + cobimetinib.. Nivolumab + ipilimumab had significantly improved clinical outcomes versus BRAF + MEK inhibitors, with benefits increasing after longer follow-up. Ongoing randomized trials directly comparing these treatments are necessary to prospectively validate these findings.

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Follow-Up Studies; Humans; Imidazoles; Immunotherapy; Ipilimumab; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Neoplasm Staging; Nivolumab; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Analysis; Vemurafenib

2019
Patient-reported outcomes in patients with resected, high-risk melanoma with BRAF
    The Lancet. Oncology, 2019, Volume: 20, Issue:5

    In the phase 3 COMBI-AD study, patients with resected, stage III melanoma with BRAF. COMBI-AD was a randomised, double-blind, placebo-controlled, phase 3 study done at 169 sites in 25 countries. Study participants were aged 18 years or older and had complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma as per American Joint Committee on Cancer 7th edition criteria, with BRAF. Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled and randomly assigned to receive dabrafenib plus trametinib (n=438) or matching placebos (n=432). Data were collected until the data cutoff for analyses of the primary endpoint (June 30, 2017). The median follow-up was 34 months (IQR 28-39) in the dabrafenib plus trametinib group and 33 months (20·5-39) in the placebo group. During the 12-month treatment phase, there were no significant or clinically meaningful changes from baseline between groups in EQ-5D-3L visual analogue scale (EQ-VAS) or utility scores. During treatment, there were no clinically meaningful differences in VAS scores or utility scores in the dabrafenib plus trametinib group between patients who did and did not experience the most common adverse events. During long-term follow-up (range 15-48 months), VAS and utility scores were similar between groups and did not differ from baseline scores. At recurrence, there were significant decreases in VAS scores in both the dabrafenib plus trametinib group (mean change -6·02, SD 20·57; p=0·0032) and the placebo group (-6·84, 20·86; p<0·0001); the mean change in utility score also differed significantly at recurrence for both groups (dabrafenib plus trametinib -0·0626, 0·1911, p<0·0001; placebo -0·0748, 0·2182, p<0·0001).. These findings show that dabrafenib plus trametinib did not affect patient-reported outcome scores during or after adjuvant treatment, and suggest that preventing or delaying relapse with adjuvant therapy could be beneficial in this setting.. Novartis.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Dermatologic Surgical Procedures; Disease Progression; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Patient Reported Outcome Measures; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life; Risk Assessment; Risk Factors; Skin Neoplasms; Time Factors

2019
A phase Ib dose-finding, pharmacokinetic study of the focal adhesion kinase inhibitor GSK2256098 and trametinib in patients with advanced solid tumours.
    British journal of cancer, 2019, Volume: 120, Issue:10

    Combined focal adhesion kinase (FAK) and MEK inhibition may provide greater anticancer effect than FAK monotherapy.. This dose-finding phase Ib study (adaptive 3 + 3 design) determined the maximum tolerated dose (MTD) of trametinib and the FAK inhibitor GSK2256098 in combination. Eligible patients had mesothelioma or other solid tumours with probable mitogen activated protein kinase pathway activation. Adverse events (AEs), dose-limiting toxicities, disease progression and pharmacokinetics/pharmacodynamics were analysed.. Thirty-four subjects were enrolled. The GSK2256098/trametinib MTDs were 500 mg twice daily (BID)/0.375 mg once daily (QD) (high/low) and 250 mg BID/0.5 mg QD (low/high). The most common AEs were nausea, diarrhoea, decreased appetite, pruritus, fatigue and rash; none were grade 4. Systemic exposure to trametinib increased when co-administered with GSK2256098, versus trametinib monotherapy; GSK2256098 pharmacokinetics were unaffected by concomitant trametinib. Median progression-free survival (PFS) was 11.8 weeks (95% CI: 6.1-24.1) in subjects with mesothelioma and was longer with Merlin-negative versus Merlin-positive tumours (15.0 vs 7.3 weeks).. Trametinib exposure increased when co-administered with GSK2256098, but not vice versa. Mesothelioma patients with loss of Merlin had longer PFS than subjects with wild-type, although support for efficacy with this combination was limited. Safety profiles were acceptable up to the MTD.

    Topics: Aged; Aminopyridines; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Focal Adhesion Protein-Tyrosine Kinases; Humans; Hydroxamic Acids; Male; Mesothelioma; Middle Aged; Neoplasms; Progression-Free Survival; Pyridones; Pyrimidinones

2019
Oral MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Patients With Acute Myeloid Leukemia With RAS Mutations: A Phase II Study.
    Clinical lymphoma, myeloma & leukemia, 2019, Volume: 19, Issue:7

    With proven single-agent activity and favorable toxicity profile of MEK-1/2 inhibition in advanced leukemia, investigation into combination strategies to overcome proposed resistance pathways is warranted. Resistance to MEK inhibition is secondary to upstream hyperactivation of RAS/RAF or activation of the PI3K/PTEN/AKT/mTOR pathway. This phase II multi-institution Cancer Therapy Evaluation Program-sponsored study was conducted to determine efficacy and safety of the combination of the ATP-competitive pan-AKT inhibitor GSK2141795, targeting the PI3K/AKT pathway, and the MEK inhibitor trametinib in RAS-mutated relapsed/refractory acute myeloid leukemia (AML).. The primary objective was to determine the proportion of patients achieving a complete remission. Secondary objectives included assessment of toxicity profile and biologic effects of this combination. Twenty-three patients with RAS-mutated AML received the combination. Two dose levels were explored (dose level 1: 2 mg trametinib, 25 mg GSK2141795 and dose level 2: 1.5 mg trametinib, 50 mg GSK2141795).. Dose level 1 was identified as the recommended phase II dose. No complete remissions were identified in either cohort. Minor responses were recognized in 5 (22%) patients. The most common drug-related toxicities included rash and diarrhea, with dose-limiting toxicities of mucositis and colitis. Longitudinal correlative assessment of the modulation of MEK and AKT pathways using reverse phase protein array and phospho-flow analysis revealed significant and near significant down-modulation of pERK and pS6, respectively. Combined MEK and AKT inhibition had no clinical activity in patients with RAS-mutated AML.. Further investigation is required to explore the discrepancy between the activity of this combination on leukemia cells and the lack of clinical efficacy.

    Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Diamines; Female; Genes, ras; Humans; Leukemia, Myeloid, Acute; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Mutation; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridones; Pyrimidinones; Treatment Outcome; Young Adult

2019
Results from a single arm, single stage phase II trial of trametinib and GSK2141795 in persistent or recurrent cervical cancer.
    Gynecologic oncology, 2019, Volume: 154, Issue:1

    Improved treatment for advanced cervical cancer is needed; currently, treatment options include combined chemotherapy and bevacizumab or pembrolizumab monotherapy for PD-L1 positive disease. PIK3CA and KRAS mutations have been reported in cervical cancers; this study therefore tested dual inhibition of PI3K and RAS signaling by combining the MEK inhibitor trametinib and the AKT inhibitor GSK2141795 in recurrent cervical cancer.. This was an investigator-initiated phase II study combining trametinib and GSK2141795 in patients with recurrent cervical cancer. Primary endpoint was best tumor response; secondary endpoints included progression free survival, overall survival, and safety assessment. Translational objectives included characterization of molecular alterations in PI3K and RAS signaling pathway genes.. Planned accrual was 35 patients; 14 patients were enrolled and received at least one dose of study drug before the study was terminated due to discontinuation of GSK2141795 development. There were no confirmed responses; 1 patient had an unconfirmed PR, 8 had stable disease, 3 had progression as best response, and 2 were unevaluable. Toxicities were mostly grade 1 and 2, although 57% of patients experienced grade 3/4 adverse events and 50% patients required a dose reduction.. The combination of trametinib and GSK2141795 was feasible but required dose holds and modifications for adverse events; however, anti-cancer activity was minimal, even in patients with PI3K or RAS pathway alterations. Although the study was terminated early after GSK2141795 development was halted, the findings in these 14 patients do not support further development of this combination in cervical cancer.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Diamines; Female; Humans; Kaplan-Meier Estimate; MAP Kinase Kinase Kinases; Middle Aged; Neoplasm Recurrence, Local; Phosphoinositide-3 Kinase Inhibitors; Progression-Free Survival; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridones; Pyrimidinones; Signal Transduction; Uterine Cervical Neoplasms

2019
Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma.
    The New England journal of medicine, 2019, 08-15, Volume: 381, Issue:7

    Patients who have unresectable or metastatic melanoma with a. We analyzed pooled extended-survival data from two trials involving previously untreated patients who had received BRAF inhibitor dabrafenib (at a dose of 150 mg twice daily) plus MEK inhibitor trametinib (2 mg once daily) in the COMBI-d and COMBI-v trials. The median duration of follow-up was 22 months (range, 0 to 76). The primary end points in the COMBI-d and COMBI-v trials were progression-free survival and overall survival, respectively.. A total of 563 patients were randomly assigned to receive dabrafenib plus trametinib (211 in the COMBI-d trial and 352 in the COMBI-v trial). The progression-free survival rates were 21% (95% confidence interval [CI], 17 to 24) at 4 years and 19% (95% CI, 15 to 22) at 5 years. The overall survival rates were 37% (95% CI, 33 to 42) at 4 years and 34% (95% CI, 30 to 38) at 5 years. In multivariate analysis, several baseline factors (e.g., performance status, age, sex, number of organ sites with metastasis, and lactate dehydrogenase level) were significantly associated with both progression-free survival and overall survival. A complete response occurred in 109 patients (19%) and was associated with an improved long-term outcome, with an overall survival rate of 71% (95% CI, 62 to 79) at 5 years.. First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Oximes; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Rate; Young Adult

2019
Neoadjuvant dabrafenib combined with trametinib for resectable, stage IIIB-C, BRAF
    The Lancet. Oncology, 2019, Volume: 20, Issue:7

    Adjuvant dabrafenib plus trametinib therapy improves relapse-free survival in patients with resected stage III melanoma. We aimed to ascertain the proportion of patients who would have a pathological response and a response according to Response Evaluation Criteria in Solid Tumors (RECIST) after neoadjuvant dabrafenib plus trametinib therapy for resectable clinical stage III melanoma.. NeoCombi was a single-arm, open-label, single-centre, phase 2 study done at Melanoma Institute Australia (Sydney, NSW, Australia). Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, clinical stage IIIB-C (American Joint Committee on Cancer [AJCC] 7th edition), BRAF. Between Aug 20, 2014, and April 19, 2017, 40 patients were screened, of whom 35 eligible patients were enrolled, received neoadjuvant dabrafenib plus trametinib, and underwent resection. At the data cutoff (Sept 24, 2018), median follow-up was 27 months (IQR 21-36). At resection, 30 (86%) patients achieved a RECIST response; 16 (46%; 95% CI 29-63) had a complete response and 14 (40%; 24-58) had a partial response. Five patients (14%; 95% CI 5-30) had stable disease, and no patients progressed. After resection and pathological evaluation, all 35 patients achieved a pathological response, of whom 17 (49%; 95% CI 31-66) patients had a complete pathological response and 18 (51%; 95% CI 34-69) had a non-complete pathological response. Treatment-related serious adverse events occurred in six (17%) of 35 patients and grade 3-4 adverse events occurred in ten (29%) patients. No treatment-related deaths were reported.. Neoadjuvant dabrafenib plus trametinib therapy could be considered in the management of RECIST-measurable resectable stage III melanoma as it led to a high proportion of patients achieving a complete response according to RECIST and a high proportion of patients achieving a complete pathological response, with no progression during neoadjuvant therapy.. GlaxoSmithKline; Novartis; National Health and Medical Research Council, Australia; and Melanoma Institute Australia.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoadjuvant Therapy; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2019
Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma.
    Nature medicine, 2019, Volume: 25, Issue:6

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Oximes; Programmed Cell Death 1 Receptor; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Young Adult

2019
A Phase I Trial of the VEGF Receptor Tyrosine Kinase Inhibitor Pazopanib in Combination with the MEK Inhibitor Trametinib in Advanced Solid Tumors and Differentiated Thyroid Cancers.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 09-15, Volume: 25, Issue:18

    Differentiated thyroid cancer (DTC) responds to VEGF receptor inhibitors. VEGF signals through RAS/RAF/MEK signaling. We evaluated the safety and efficacy of the VEGF receptor inhibitor pazopanib and MEK inhibitor trametinib in advanced solid tumors and DTC.. Patients with advanced solid tumors were enrolled in a phase I, multicenter trial with a DTC expansion cohort. Patients received pazopanib 400-800 mg and trametinib 1-2 mg daily. Efficacy in the expansion cohort was assessed with objective response (OR) at 6 months of treatment.. Twenty-six patients were enrolled in five dose levels. MTD was not reached; the recommended phase II dose was pazopanib 800 mg orally and trametinib 2 mg orally every day. There was one dose-limiting toxicity on dose level 1 with grade 3 fatigue and muscle weakness. Common grade 3 adverse events were elevated transaminases (19%), diarrhea (15%), hypertension (12%), and fatigue (8%). Thirteen patients were enrolled in the DTC cohort; OR was 33% (95% confidence interval, 9.9, 65.1%) and median progression-free survival was 10.7 months. The cohort was terminated after planned interim analysis suggested insufficiently increased activity against the historical control of pazopanib alone. Reduction in tumor diameter negatively correlated with p-ERK change in tumor (Spearman ρ = -0.71;. Pazopanib + trametinib was tolerable at full single-agent doses with clinical activity in DTC but did not achieve the prespecified response rate target.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Female; Humans; Indazoles; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Pyrimidinones; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Thyroid Neoplasms; Treatment Outcome

2019
Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia.
    Blood advances, 2019, 07-09, Volume: 3, Issue:13

    Topics: Acetates; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Molecular Targeted Therapy; Piperidones; Proto-Oncogene Proteins c-mdm2; Pyridones; Pyrimidinones; Recurrence; Treatment Outcome

2019
Dual MEK/AKT inhibition with trametinib and GSK2141795 does not yield clinical benefit in metastatic NRAS-mutant and wild-type melanoma.
    Pigment cell & melanoma research, 2018, Volume: 31, Issue:1

    Aberrant MAPK and PI3K pathway signaling may drive the malignant phenotype in NRAS-mutant and BRAF

    Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Diamines; Female; GTP Phosphohydrolases; Humans; Male; MAP Kinase Kinase 1; Melanoma; Membrane Proteins; Middle Aged; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Rate; Treatment Outcome; Young Adult

2018
Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2018, 03-01, Volume: 36, Issue:7

    Purpose To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600-mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. Patients and Methods BRAF inhibitor-naive patients with BRAF V600-mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2). Patients who received D monotherapy could cross over to D + T 150/2 postprogression. Efficacy and safety were analyzed 4 and 5 years after initiation in patients with ≥ 5 years of follow-up. Results As of October 13, 2016, 18 patients who received D + T 150/2 remained in the study (13 [24%] of 54 enrolled at this dose plus five [11%] of 45 initially administered D who crossed over to D + T). With D + T 150/2, overall survival (OS; 4 years, 30%; 5 years, 28%) and progression-free survival (4 and 5 years, both 13%) appeared to stabilize with extended follow-up. Increased OS was observed in patients who received D + T with baseline normal lactate dehydrogenase (5 years, 45%) and normal lactate dehydrogenase with fewer than three organ sites with metastasis (5 years, 51%). With extended follow-up, one additional patient who received D + T 150/2 improved from a partial to a complete response. No new safety signals were observed. Conclusion This 5-year analysis represents the longest follow-up to date with BRAF + MEK inhibitor combination therapy in BRAF V600-mutant MM. Consistent with trends observed in landmark analyses with shorter follow-up, this therapy elicits durable plateaus of long-term OS and progression-free survival that last ≥ 5 years in some patients with MM.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

2018
Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2018, 01-01, Volume: 36, Issue:1

    Purpose We report the efficacy and safety of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy in BRAF V600E-mutated anaplastic thyroid cancer, a rare, aggressive, and highly lethal malignancy with poor patient outcomes and no systemic therapies with clinical benefit. Methods In this phase II, open-label trial, patients with predefined BRAF V600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. The primary end point was investigator-assessed overall response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Results Sixteen patients with BRAF V600E-mutated anaplastic thyroid cancer were evaluable (median follow-up, 47 weeks; range, 4 to 120 weeks). All patients had received prior radiation treatment and/or surgery, and six had received prior systemic therapy. The confirmed overall response rate was 69% (11 of 16; 95% CI, 41% to 89%), with seven ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached as a result of a lack of events, with 12-month estimates of 90%, 79%, and 80%, respectively. The safety population was composed of 100 patients who were enrolled with seven rare tumor histologies. Common adverse events were fatigue (38%), pyrexia (37%), and nausea (35%). No new safety signals were detected. Conclusion Dabrafenib plus trametinib is the first regimen demonstrated to have robust clinical activity in BRAF V600E-mutated anaplastic thyroid cancer and was well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Fatigue; Female; Fever; Humans; Imidazoles; Male; Middle Aged; Mutation; Nausea; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Carcinoma, Anaplastic; Young Adult

2018
Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine.
    Cancer science, 2018, Volume: 109, Issue:1

    Gemcitabine-based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second-line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non-competitive inhibitor of MEK1/MEK2. In this phase IIa open-label, single-arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine-based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12-week non-PD rate. Secondary assessments included safety, progression-free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non-PD rate at week 12 was 10% (95% confidence interval, 1.2-31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6-12.1) and 1-year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end-point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss-of-function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.

    Topics: Administration, Oral; Aged; Aged, 80 and over; Ampulla of Vater; Bile Duct Neoplasms; Biliary Tract Neoplasms; DNA-Binding Proteins; Exome Sequencing; Female; Gallbladder Neoplasms; Humans; Male; Middle Aged; Neurofibromin 1; Nuclear Proteins; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Survival Analysis; Transcription Factors; Treatment Outcome

2018
Model based analysis of the heterogeneity in the tumour size dynamics differentiates vemurafenib, dabrafenib and trametinib in metastatic melanoma.
    Cancer chemotherapy and pharmacology, 2018, Volume: 81, Issue:2

    Explore the heterogeneity in dynamics of tumour response to vemurafenib, dabrafenib and trametinib using routinely collected clinical trial imaging data.. Time-series imaging data from the phase III studies of vemurafenib, dabrafenib and trametinib were collected through a data repository. A mathematical model based on basic mechanisms of tumour growth was placed within a statistical modelling framework to analyse the data.. The analysis revealed: (1) existence of homogeneity in drug response and resistance development within a patient; (2) tumour shrinkage rate does not relate to rate of resistance development; (3) vemurafenib and dabrafenib, two BRAF inhibitors, have different variability in tumour shrinkage rates.. Overall these results show how analysis of the dynamics of individual lesions can shed light on the within and between patient differences in tumour shrinkage and resistance rates, which could be used to gain a macroscopic understanding of tumour heterogeneity.

    Topics: Algorithms; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Imidazoles; Melanoma; Models, Theoretical; Neoplasm Metastasis; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

2018
Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial.
    The Lancet. Oncology, 2018, Volume: 19, Issue:2

    Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation.. We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were adult patients (aged ≥18 years) with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAF. Between Oct 23, 2014, and April 13, 2016, we randomly assigned seven patients to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib. The trial was stopped early after a prespecified interim safety analysis that occurred after a quarter of the participants had been accrued revealed significantly longer event-free survival with neoadjuvant plus adjuvant dabrafenib and trametinib than with standard of care. After a median follow-up of 18·6 months (IQR 14·6-23·1), significantly more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group; median event-free survival was 19·7 months [16·2-not estimable] vs 2·9 months [95% CI 1·7-not estimable]; hazard ratio 0·016, 95% CI 0·00012-0·14, p<0·0001). Neoadjuvant plus adjuvant dabrafenib and trametinib were well tolerated with no occurrence of grade 4 adverse events or treatment-related deaths. The most common adverse events in the neoadjuvant plus adjuvant dabrafenib and trametinib group were expected grade 1-2 toxicities including chills (12 patients [92%]), headache (12 [92%]), and pyrexia (ten [77%]). The most common grade 3 adverse event was diarrhoea (two patients [15%]).. Neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival versus standard of care in patients with high-risk, surgically resectable, clinical stage III-IV melanoma. Although the trial finished early, limiting generalisability of the results, the findings provide proof-of-concept and support the rationale for further investigation of neoadjuvant approaches in this disease. This trial is currently continuing accrual as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib.. Novartis Pharmaceuticals Corporation.

    Topics: Academic Medical Centers; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cancer Care Facilities; Chemotherapy, Adjuvant; Confidence Intervals; Disease-Free Survival; Humans; Imidazoles; Melanoma; Middle Aged; Mohs Surgery; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Oximes; Prognosis; Pyridones; Pyrimidinones; Risk Assessment; Skin Neoplasms; Standard of Care; Survival Analysis; Texas; Treatment Outcome

2018
Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma.
    The Journal of dermatology, 2018, Volume: 45, Issue:4

    The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end-point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end-points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end-points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator-assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9-99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Humans; Imidazoles; Japan; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Young Adult

2018
Combined BRAF, EGFR, and MEK Inhibition in Patients with
    Cancer discovery, 2018, Volume: 8, Issue:4

    Although BRAF inhibitor monotherapy yields response rates >50% in

    Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Imidazoles; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Oximes; Panitumumab; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2018
Phase 1B Study of Momelotinib Combined With Trametinib in Metastatic, Kirsten Rat Sarcoma Viral Oncogene Homolog-Mutated Non-Small-Cell Lung Cancer After Platinum-Based Chemotherapy Treatment Failure.
    Clinical lung cancer, 2018, Volume: 19, Issue:6

    Specific treatment options are lacking for Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated non-small-cell lung cancer (NSCLC) despite treatment advances in other mutation-driven subgroups.. In this study we evaluated the multitargeted Janus kinase/TANK-binding kinase 1 (TBK1) inhibitor momelotinib combined with the mitogen/extracellular signal-related kinase (MEK)1/MEK2 inhibitor trametinib in patients with platinum-treated, refractory, metastatic, KRAS-mutated NSCLC. Dose escalations (3 + 3 design) were conducted with momelotinib in combination with trametinib 1.0 mg once daily, then with trametinib in combination with the maximum tolerated dose (MTD) of momelotinib. MTD was determined from dose-limiting toxicity (DLT) during patients' first 28-day cycle. Safety was the primary end point, and efficacy parameters, including disease control rate (DCR) at 8 weeks, were secondary end points.. Twenty-one patients were enrolled (median age: 68 years; 14 [66.7%] female). The MTD was momelotinib 150 mg twice daily in combination with trametinib 1.0 mg once daily. DLTs that determined the MTD were increased alanine aminotransferase and fatigue. The most common adverse events of any grade were nausea (n = 14 [66.7%]), diarrhea (n = 11 [52.4%]), and fatigue (n = 11 [52.4%]). The most common Grade ≥3 event was hypoxia (n = 3 [14.3%]). No patients achieved objective response. DCR at 8 weeks was 12 patients (57.1%) (90% confidence interval [CI], 37.2%-75.5%). Median progression-free and overall survival were 3.6 months (90% CI, 2.2-5.6 months) and 7.4 months (90% CI, 4.0-15.3 months), respectively. Maximum momelotinib plasma concentrations were reached 1 to 2 hours after dosing, but were insufficient to achieve significant TBK1 inhibition.. The additional use of momelotinib with trametinib does not improve on the activity of single-agent trametinib in KRAS-mutated NSCLC on the basis of historic data.

    Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Carcinoma, Non-Small-Cell Lung; Female; Humans; Janus Kinases; Lung Neoplasms; Male; MAP Kinase Kinase 1; Middle Aged; Mutation; Neoplasm Metastasis; Platinum; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidines; Pyrimidinones; Treatment Failure

2018
Is time to progression associated with post-progression survival in previously treated metastatic non-small cell lung cancer with BRAF V600E mutation? A secondary analysis of phase II clinical trial data.
    BMJ open, 2018, 08-17, Volume: 8, Issue:8

    Longer time to progression (TTP) is associated with prolonged post-progression survival (PPS) in anaplastic lymphoma kinase+non-small cell lung cancer (NSCLC). This study evaluated whether TTP is associated with PPS among previously treated patients with metastatic v-Raf murine sarcoma viral oncogene homolog B V600E NSCLC receiving dabrafenib as monotherapy or in combination with trametinib.. Secondary analysis of phase II clinical trial data.. Patients who experienced disease progression treated with dabrafenib monotherapy or in combination with trametinib as second line or later in an open-label, non-randomised, phase II study.. The primary outcome was the TTP-PPS association. PPS was assessed with Kaplan-Meier analysis among patients with shorter versus longer TTP (< or ≥6 months). The TTP-PPS association was quantified in the Cox models adjusting for clinical covariates.. Of the 84 included patients who progressed on dabrafenib monotherapy (n=57) or combination therapy (n=27), 60 (71%) died during post-progression follow-up. Patients with TTP ≥6 months experienced significantly longer PPS compared with those with TTP <6 months (median PPS: 9.5 vs 2.7 months, log-rank p<0.001). Each 3 months of longer TTP was associated with a 32% lower hazard of death following progression (HR 0.68, 95% CI 0.52 to 0.88) in the multivariable Cox model. Similar associations were seen in each treatment arm.. A longer TTP duration after treatment with dabrafenib monotherapy or combination therapy was associated with significantly longer PPS duration.. NCT01336634; Post-results.

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease Progression; Female; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2018
Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2018, 12-10, Volume: 36, Issue:35

    Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47;. In this phase III trial, patients with resected. At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). Distant metastasis-free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67). The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration.. Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.

    Topics: Adjuvants, Immunologic; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Imidazoles; Internationality; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sex Factors; Skin Neoplasms; Time Factors; Treatment Outcome

2018
Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2017, Jul-01, Volume: 28, Issue:7

    Previous analysis of COMBI-d (NCT01584648) demonstrated improved progression-free survival (PFS) and overall survival (OS) with combination dabrafenib and trametinib versus dabrafenib monotherapy in BRAF V600E/K-mutant metastatic melanoma. This study was continued to assess 3-year landmark efficacy and safety after ≥36-month follow-up for all living patients.. This double-blind, phase 3 study enrolled previously untreated patients with BRAF V600E/K-mutant unresectable stage IIIC or stage IV melanoma. Patients were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) or dabrafenib plus placebo. The primary endpoint was PFS; secondary endpoints were OS, overall response, duration of response, safety, and pharmacokinetics.. Between 4 May and 30 November 2012, a total of 423 of 947 screened patients were randomly assigned to receive dabrafenib plus trametinib (n = 211) or dabrafenib monotherapy (n = 212). At data cut-off (15 February 2016), outcomes remained superior with the combination: 3-year PFS was 22% with dabrafenib plus trametinib versus 12% with monotherapy, and 3-year OS was 44% versus 32%, respectively. Twenty-five patients receiving monotherapy crossed over to combination therapy, with continued follow-up under the monotherapy arm (per intent-to-treat principle). Of combination-arm patients alive at 3 years, 58% remained on dabrafenib plus trametinib. Three-year OS with the combination reached 62% in the most favourable subgroup (normal lactate dehydrogenase and <3 organ sites with metastasis) versus only 25% in the unfavourable subgroup (elevated lactate dehydrogenase). The dabrafenib plus trametinib safety profile was consistent with previous clinical trial observations, and no new safety signals were detected with long-term use.. These data demonstrate that durable (≥3 years) survival is achievable with dabrafenib plus trametinib in patients with BRAF V600-mutant metastatic melanoma and support long-term first-line use of the combination in this setting.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; Double-Blind Method; Drug Administration Schedule; Humans; Imidazoles; Kaplan-Meier Estimate; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Risk Factors; Skin Neoplasms; Time Factors; Treatment Outcome

2017
Dabrafenib plus trametinib in patients with BRAF
    The Lancet. Oncology, 2017, Volume: 18, Issue:7

    Dabrafenib plus trametinib improves clinical outcomes in BRAF. This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF. Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]).. Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAF. Novartis.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Fever; Headache; Humans; Imidazoles; Magnetic Resonance Imaging; Male; Melanoma; Middle Aged; Mutation; Oximes; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Stroke Volume; Young Adult

2017
Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials.
    European journal of cancer (Oxford, England : 1990), 2017, Volume: 82

    Understanding predictors of long-term benefit with currently available melanoma therapies is the key for optimising individualised treatments. A prior pooled analysis of dabrafenib plus trametinib (D + T)-randomised trials (median follow-up, 20.0 months) identified baseline lactate dehydrogenase (LDH) and number of organ sites with metastasis as predictive factors for progression-free (PFS) and overall (OS) survival. However, longer-term follow-up analyses are needed to confirm which patients treated with D + T can achieve maximum benefit.. Three-year landmark data were retrospectively pooled for D + T patients in phase 3 trials (COMBI-d [NCT01584648]; COMBI-v [NCT01597908]). Univariate and multivariate analyses assessed prognostic values of predefined baseline factors; regression tree analysis determined hierarchy and interactions between variables.. Long-term pooled outcomes were consistent with individual trial results (N = 563; 3-year PFS, 23%; 3-year OS, 44%). Baseline LDH level and number of organ sites remained strongly associated with and/or predictive of PFS and OS. In addition, baseline sum of lesion diameters (SLD) was identified as a predictor for progression. In the most favourable prognostic group (normal LDH, SLD <66 mm, <3 organ sites; n = 183/563 [33%]), 3-year PFS was 42%. Baseline number of organ sites was also predictive of outcomes in patients with PFS ≥ 6 months.. Using the largest phase 3 data set available for BRAF/MEK inhibitor combination therapy in melanoma, these results demonstrate that durable responses lasting ≥3 years are possible in subsets of patients with BRAF-mutant melanoma receiving D + T. Although the best predictive model evolved with longer follow-up, factors predicting clinical outcomes with the combination remained consistent with previous analyses.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; L-Lactate Dehydrogenase; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Oximes; Predictive Value of Tests; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Risk Factors; Survival Analysis

2017
Perioperative BRAF inhibitors in locally advanced stage III melanoma.
    Journal of surgical oncology, 2017, Volume: 116, Issue:7

    Stage III malignant melanoma is a heterogeneous disease where those cases deemed marginally resectable or irresecatble are frequently incurable by surgery alone. Targeted therapy takes advantage of the high incidence of BRAF mutations in melanomas, most notably the V600E mutation. These agents have rarely been used in a neoadjuvant setting prior to surgery.. Thirteen consecutive patients with confirmed BRAF. Overall, 12/13 patients showed a marked clinical responsiveness to medical treatment, enabling a macroscopically successful resection in all cases. Four patients had a complete pathological response with no viable tumor evident in the resected specimens and eight patients showed evidence of minimally residual tumor with extensive tumoral necrosis and fibrosis. One patient progressed and died before surgery. At a median follow up of 20 months, 10 patients remain free of disease.. Perioperative treatment with BRAF inhibiting agents in BRAFV600E mutated Stage III melanoma patients facilitates surgical resection and affords satisfactory disease free survival.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Oximes; Perioperative Care; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2017
Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma.
    The New England journal of medicine, 2017, 11-09, Volume: 377, Issue:19

    Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations.. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse-free survival. Secondary end points included overall survival, distant metastasis-free survival, freedom from relapse, and safety.. At a median follow-up of 2.8 years, the estimated 3-year rate of relapse-free survival was 58% in the combination-therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3-year overall survival rate was 86% in the combination-therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis-free survival and freedom from relapse were also higher in the combination-therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma.. Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov, NCT01682083 ; EudraCT number, 2012-001266-15 .).

    Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Female; Humans; Imidazoles; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Analysis; Young Adult

2017
Dabrafenib plus trametinib in patients with previously untreated BRAF
    The Lancet. Oncology, 2017, Volume: 18, Issue:10

    BRAF. In this phase 2, sequentially enrolled, multicohort, multicentre, non-randomised, open-label study, adults (≥18 years of age) with previously untreated metastatic BRAF. Between April 16, 2014, and Dec 28, 2015, 36 patients were enrolled and treated with first-line dabrafenib plus trametinib. Median follow-up was 15·9 months (IQR 7·8-22·0) at the data cutoff (April 28, 2017). The proportion of patients with investigator-assessed confirmed overall response was 23 (64%, 95% CI 46-79), with two (6%) patients achieving a complete response and 21 (58%) a partial response. All patients had one or more adverse event of any grade, and 25 (69%) had one or more grade 3 or 4 event. The most common (occurring in more than two patients) grade 3 or 4 adverse events were pyrexia (four [11%]), alanine aminotransferase increase (four [11%]), hypertension (four [11%]), and vomiting (three [8%]). Serious adverse events occurring in more than two patients included alanine aminotransferase increase (five [14%]), pyrexia (four [11%]), aspartate aminotransferase increase (three [8%]), and ejection fraction decrease (three [8%]). One fatal serious adverse event deemed unrelated to study treatment was reported (cardiorespiratory arrest).. Dabrafenib plus trametinib represents a new therapy with clinically meaningful antitumour activity and a manageable safety profile in patients with previously untreated BRAF. Novartis.

    Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Confidence Intervals; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Lung Neoplasms; Maximum Tolerated Dose; Middle Aged; Mutation; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Oximes; Prognosis; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

2017
A Novel Spectroscopically Determined Pharmacodynamic Biomarker for Skin Toxicity in Cancer Patients Treated with Targeted Agents.
    Cancer research, 2017, 01-15, Volume: 77, Issue:2

    Raman spectroscopy is a noninvasive and label-free optical technique that provides detailed information about the molecular composition of a sample. In this study, we evaluated the potential of Raman spectroscopy to predict skin toxicity due to tyrosine kinase inhibitors treatment. We acquired Raman spectra of skin of patients undergoing treatment with MEK, EGFR, or BRAF inhibitors, which are known to induce severe skin toxicity; for this pilot study, three patients were included for each inhibitor. Our algorithm, based on partial least squares-discriminant analysis (PLS-DA) and cross-validation by bootstrapping, discriminated to variable degrees spectra from patient suffering and not suffering cutaneous adverse events. For MEK and EGFR inhibitors, discriminative power was more than 90% in the viable epidermis skin layer; whereas for BRAF inhibitors, discriminative power was 71%. There was a 81.5% correlation between blood drug concentration and Raman signature of skin in the case of EGFR inhibitors and viable epidermis skin layer. Our results demonstrate the power of Raman spectroscopy to detect apparition of skin toxicity in patients treated with tyrosine kinase inhibitors at levels not detectable via dermatological inspection and histological evaluation. Cancer Res; 77(2); 557-65. ©2016 AACR.

    Topics: Aged; Algorithms; Antineoplastic Agents; Area Under Curve; Biomarkers; Drug Eruptions; Erlotinib Hydrochloride; Female; Humans; Imidazoles; Indoles; Male; Middle Aged; Oximes; Pilot Projects; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; ROC Curve; Sensitivity and Specificity; Skin; Spectrum Analysis, Raman; Sulfonamides; Vemurafenib

2017
Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex.
    Cancer discovery, 2017, Volume: 7, Issue:3

    Targeting the dysregulated BRAF-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRAF and MEK, resistance develops often involving nongenomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in patients with triple-negative breast cancer (TNBC) induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTK) comparing tumor samples before and after one week of treatment. In preclinical models, MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation, and p300 that drives transcriptional adaptation. Inhibition of the P-TEFb-associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts, and syngeneic mouse TNBC models. Pharmacologic targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance.

    Topics: Animals; Antineoplastic Agents; Azepines; Cell Cycle Proteins; Cell Line, Tumor; Discoidin Domain Receptor 1; DNA Methylation; Drug Resistance, Neoplasm; Drug Synergism; Enhancer Elements, Genetic; Epigenesis, Genetic; Female; Heterocyclic Compounds, 4 or More Rings; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mice, Inbred BALB C; Mice, SCID; Molecular Targeted Therapy; Nuclear Proteins; Positive Transcriptional Elongation Factor B; Pyridones; Pyrimidinones; RNA Interference; Transcription Factors; Triazoles; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

2017
Digoxin Plus Trametinib Therapy Achieves Disease Control in BRAF Wild-Type Metastatic Melanoma Patients.
    Neoplasia (New York, N.Y.), 2017, Volume: 19, Issue:4

    This is the first prospective study of a combination therapy involving a cardenolide and a MEK inhibitor for metastatic melanoma. Whereas BRAF mutant melanomas can exhibit profound responses to treatment with BRAF and MEK inhibitors, there are fewer options for BRAF wild-type melanomas. In preclinical studies, we discovered that cardenolides synergize with MEK inhibitor to promote the regression of patient-derived xenografts irrespective of BRAF mutation status. We therefore conducted a phase 1B study of digoxin 0.25 mg and trametinib 2 mg given orally once daily in 20 patients with advanced, refractory, BRAF wild-type melanomas. The most common adverse events were rash, diarrhea, nausea, and fatigue. The response rate was 4/20 or 20% with response durations of 2, 4, 6, and 8 months. The disease control rate (including partial responses and stable disease) was 13/20 or 65% of patients, including 5/6 or 83% of patients with NRAS mutant melanomas and 8/14 or 57% of NRAS wild-type melanomas. Patients with stable disease had disease control for 2, 2, 2, 4, 5, 6, 7, 10, and 10 months. Xenografts from four patients recapitulated the treatment responses observed in patients. Based on these pilot results, an expansion arm of digoxin plus MEK inhibitor is warranted for NRAS mutant metastatic melanoma patients who are refractory or intolerant of immunotherapy.. Digoxin plus trametinib is well tolerated and achieves a high rate of disease control in BRAF wild-type metastatic melanoma patients.

    Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Combined Chemotherapy Protocols; Digoxin; Disease Models, Animal; Female; Humans; Male; Melanoma; Mice; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retreatment; Treatment Outcome; Xenograft Model Antitumor Assays

2017
Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2016, Mar-10, Volume: 34, Issue:8

    To report the overall survival (OS) and clinical characteristics of BRAF inhibitor-naive long-term responders and survivors treated with dabrafenib plus trametinib in a phase I and II study of patients with BRAF V600 mutation-positive metastatic melanoma.. BRAF inhibitor-naive patients treated with dabrafenib 150 mg twice daily plus trametinib 2 mg daily (the 150/2 group) from the non-randomly assigned (part B) and randomly assigned (part C) cohorts of the study were analyzed for progression-free and OS separately. Baseline characteristics and factors on treatment were analyzed for associations with durable responses and OS.. For BRAF inhibitor-naive patients in the 150/2 groups (n = 78), the progression-free survival at 1, 2, and 3 years was 44%, 22%, and 18%, respectively, for part B (n = 24) and 41%, 25%, and 21%, respectively, for part C (n = 54). Median OS was 27.4 months in part B and 25 months in part C. OS at 1, 2, and 3 years was 72%, 60%, and 47%, respectively, for part B and 80%, 51%, and 38%, respectively, for part C. Prolonged survival was associated with metastases in fewer than three organ sites and lower baseline lactate dehydrogenase. OS at 3 years was 62% in patients with normal baseline lactate dehydrogenase and 63% in patients with a complete response.. Dabrafenib plus trametinib results in a median OS of more than 2 years in BRAF inhibitor-naive patients with BRAF V600 mutation-positive metastatic melanoma, and approximately 20% were progression free at 3 years. Durable responses occurred in patients with good prognostic features at baseline, which may be predictive.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

2016
[Development of serous retinopathy during therapy of a metastatic cutaneous melanoma].
    Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft, 2016, Volume: 113, Issue:10

    Inhibitors of the mitogen-activated protein kinase (MAPK) signal pathway have decisively improved the prognosis of metastatic cutaneous melanoma in patients with an activating mutation in position V600 of the BRAF gene. We report on a patient who was regularly examined in our clinic while participating in a randomized blinded clinical trial. The aim of this trial was to examine the effectiveness and tolerability of a combination of the BRAF inhibitor dabrafenib and the MAPK kinase (MEK) inhibitor trametinib compared with a monotherapy with dabrafenib (plus placebo). During therapy the patient developed a diffuse neuroretinal detachment which could not be completely reversed after discontinuation of the study medication.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Central Serous Chorioretinopathy; Diagnosis, Differential; Female; Humans; Imidazoles; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Single-Blind Method; Skin Neoplasms; Treatment Outcome

2016
Population pharmacokinetics and exposure-response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma.
    Cancer chemotherapy and pharmacology, 2016, Volume: 77, Issue:4

    To characterize the pharmacokinetics of oral trametinib, a first in class MEK inhibitor, identify covariates, and describe the relationship between exposure and clinical effects in patients with BRAF V600 metastatic melanoma.. Trametinib concentrations obtained in three clinical studies were included in the population pharmacokinetic analysis. Trametinib 2 mg once daily was administered in the Phase 2 and 3 studies. The impact of exposure [trough (C min) or average concentration] on response rates and progression-free survival (PFS) was examined.. Plasma concentrations (n = 3120) obtained in 493 patients were described using a two-compartment model. Trametinib oral clearance was lower in women relative to men (1.26-fold) and increased with body weight. There was no significant effect of age, mild or moderate renal impairment, or mild hepatic impairment on oral clearance. Between-subject variability was low (24 %). The number of responders was consistent across median exposure range, although tended to be lower at trough concentration <10 ng/mL. Disease stage was found to be a significant predictor of response with a lower response rate in patients with disease stage of M1c. Lactate dehydrogenase was significant in the analysis of PFS. Patients with observed C min above the median had longer PFS than those below median based on Phase 2 study (median 10.6 ng/mL), while the effect of exposure was not statistically significant in the Phase 3 study (median 13.6 ng/mL).. No dosage adjustments are required with any of the covariates tested. Clinical efficacy was associated with trametinib trough concentrations greater than 10 ng/mL.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Humans; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2016
Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies.
    Cancer, 2016, 06-15, Volume: 122, Issue:12

    RAS/RAF/mitogen-activated protein kinase activation is common in myeloid malignancies. Trametinib, a mitogen-activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, was evaluated for safety and clinical activity in patients with relapsed/refractory leukemias.. This phase 1/2 study accrued patients with any relapsed/refractory leukemia in phase 1. In phase 2, this study accrued patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) with NRAS or KRAS mutations (cohort 1); patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) with a RAS wild-type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohorts 3).. The most commonly reported treatment-related adverse events were diarrhea, rash, nausea, and increased alanine aminotransferase levels. The phase 2 recommended dose for Trametinib was 2 mg orally daily. The overall response rates were 20%, 3%, and 27% for cohorts 1, 2, and 3, respectively, and this indicated preferential activity among RAS-mutated myeloid malignancies. Repeated cycles of trametinib were well tolerated with manageable or reversible toxicities; these results were similar to those of other trametinib studies.. The selective, single-agent activity of trametinib against RAS-mutated myeloid malignancies validates its therapeutic potential. Combination strategies based on a better understanding of the hierarchical role of mutations and signaling in myeloid malignancies are likely to improve the response rate and duration. Cancer 2016;122:1871-9. © 2016 American Cancer Society.

    Topics: Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Humans; Kaplan-Meier Estimate; Leukemia; Leukemia, Myeloid, Acute; MAP Kinase Signaling System; Middle Aged; Mutation; Myelodysplastic Syndromes; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Recurrence; Young Adult

2016
Hair and nail adverse events during treatment with targeted therapies for metastatic melanoma.
    European journal of dermatology : EJD, 2016, Jun-01, Volume: 26, Issue:3

    Targeted therapies for melanoma have shown clinical benefit in increasing the survival of metastatic patients. Cutaneous adverse events have been reported, but hair and nail data have been rarely detailed. Patients treated with BRAF and MEK inhibitors for metastatic melanoma underwent dermatological evaluation before the start of each treatment and after every four weeks. Pull test, global photography, dermoscopy/trichoscopy and scalp biopsy were performed. Appendages adverse events were graded using the National Cancer Institute's Common Terminology Criteria. Of the 24 patients included, 14 underwent treatment with a selective BRAF inhibitor; 10 received a combined treatment (dabrafenib/trametinib). Adnexal adverse events were common in the group of patients receiving vemurafenib, and included hair kinking, acute hair loss, and hair colour changes, often present in association, classified as G2 in three patients and G1 in eight. Dabrafenib alone induced hair kinking and colour changes in 60% of the patients. Combined treatment with dabrafenib/trametinib did not induce hair changes. Onycholysis was the most common nail side effect, and the unique side effect of dabrafenib (alone or in combination). Vemurafenib also induced acute paronychia and brittle nails. All nail side effects were graded as G1. Hair and nail side effects during targeted therapy for melanoma are not rare. The early recognition and cure of such side effects by dermatologists is of benefit to ensure the need for dose reduction or drug discontinuation.

    Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Eruptions; Female; Hair Diseases; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Nail Diseases; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; raf Kinases; Skin Neoplasms; Sulfonamides; Vemurafenib

2016
Clinical, Molecular, and Immune Analysis of Dabrafenib-Trametinib Combination Treatment for BRAF Inhibitor-Refractory Metastatic Melanoma: A Phase 2 Clinical Trial.
    JAMA oncology, 2016, Aug-01, Volume: 2, Issue:8

    Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi)-refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development.. To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractory metastatic melanoma.. Single-center, single-arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy.. Patients were treated with dabrafenib (150 mg, twice daily) and trametinib (2 mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600.. The primary end point was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points.. A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73% vs 11% for ≤6 months; P = .02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75% vs 18% for no decrease; P = .02) but not with pretreatment mitogen-activated protein kinase (MAPK) pathway mutations or activation. Biopsy specimens obtained during treatment demonstrated that CombiDT therapy failed to achieve significant MAPK pathway inhibition or immune infiltration in most patients.. The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT in patients with BRAFi-refractory metastatic melanoma. Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of CombiDT in this setting. Circulating BRAF V600 is a promising early biomarker of clinical response.. clinicaltrials.gov Identifier: NCT01619774.

    Topics: Adaptor Proteins, Signal Transducing; Adult; Antineoplastic Agents; B7-H1 Antigen; CD8 Antigens; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Imidazoles; Immunohistochemistry; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Oximes; Phosphorylation; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Ribosomal Protein S6; Signal Transduction; Skin Neoplasms; Treatment Outcome

2016
Adjusting for treatment switching in the METRIC study shows further improved overall survival with trametinib compared with chemotherapy.
    Cancer medicine, 2016, Volume: 5, Issue:5

    Trametinib, a selective inhibitor of mitogen-activated protein kinase kinase 1 (MEK1) and MEK2, significantly improves progression-free survival compared with chemotherapy in patients with BRAF V600E/K mutation-positive advanced or metastatic melanoma (MM). However, the pivotal clinical trial permitted randomized chemotherapy control group patients to switch to trametinib after disease progression, which confounded estimates of the overall survival (OS) advantage of trametinib. Our purpose was to estimate the switching-adjusted treatment effect of trametinib for OS and assess the suitability of each adjustment method in the primary efficacy population. Of the patients randomized to chemotherapy, 67.4% switched to trametinib. We applied the rank-preserving structural failure time model, inverse probability of censoring weights, and a two-stage accelerated failure time model to obtain estimates of the relative treatment effect adjusted for switching. The intent-to-treat (ITT) analysis estimated a 28% reduction in the hazard of death with trametinib treatment (hazard ratio [HR], 0.72; 95% CI, 0.52-0.98) for patients in the primary efficacy population (data cut May 20, 2013). Adjustment analyses deemed plausible provided OS HR point estimates ranging from 0.48 to 0.53. Similar reductions in the HR were estimated for the first-line metastatic subgroup. Treatment with trametinib, compared with chemotherapy, significantly reduced the risk of death and risk of disease progression in patients with BRAF V600E/K mutation-positive advanced melanoma or MM. Adjusting for switching resulted in lower HRs than those obtained from standard ITT analyses. However, CI are wide and results are sensitive to the assumptions associated with each adjustment method.

    Topics: Antineoplastic Agents; Dacarbazine; Disease Progression; Drug Substitution; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Middle Aged; Mutation; Paclitaxel; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Analysis

2016
Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial.
    The Lancet. Oncology, 2016, Volume: 17, Issue:7

    BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAF(V600E)-mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAF(V600E)-mutant NSCLC might improve efficacy over BRAF inhibitor monotherapy based on observations in BRAF(V600)-mutant melanoma. We aimed to assess the antitumour activity and safety of dabrafenib plus trametinib in patients with BRAF(V600E)-mutant NSCLC.. In this phase 2, multicentre, non-randomised, open-label study, we enrolled adult patients (aged ≥18 years) with pretreated metastatic stage IV BRAF(V600E)-mutant NSCLC who had documented tumour progression after at least one previous platinum-based chemotherapy and had had no more than three previous systemic anticancer therapies. Patients with previous BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were allowed to enrol only if the lesions were asymptomatic, untreated (or stable more than 3 weeks after local therapy if treated), and measured less than 1 cm. Enrolled patients received oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) in continuous 21-day cycles until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was investigator-assessed overall response, which was assessed by intention to treat in the protocol-defined population (patients who received second-line or later treatment); safety was also assessed in this population and was assessed at least once every 3 weeks, with adverse events, laboratory values, and vital signs graded according to the Common Terminology Criteria for Adverse Events version 4.0. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634.. Between Dec 20, 2013, and Jan 14, 2015, 59 patients from 30 centres in nine countries across North America, Europe, and Asia met eligibility criteria. Two patients who had previously been untreated due to protocol deviation were excluded; thus, 57 eligible patients were enrolled. 36 patients (63·2% [95% CI 49·3-75·6]) achieved an investigator-assessed overall response. Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia in nine (16%), anaemia in three (5%), confusional state in two (4%), decreased appetite in two (4%), haemoptysis in two (4%), hypercalcaemia in two (4%), nausea in two (4%), and cutaneous squamous cell carcinoma in two (4%). The most common grade 3-4 adverse events were neutropenia in five patients (9%), hyponatraemia in four (7%), and anaemia in three (5%). Four patients died during the study from fatal adverse events judged to be unrelated to treatment (one retroperitoneal haemorrhage, one subarachnoid haemorrhage, one respiratory distress, and one from disease progression that was more severe than typical progression, as assessed by the investigator).. Dabrafenib plus trametinib could represent a new targeted therapy with robust antitumour activity and a manageable safety profile in patients with BRAF(V600E)-mutant NSCLC.. GlaxoSmithKline.

    Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Female; Follow-Up Studies; Humans; Imidazoles; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

2016
Phase 1 study to evaluate the effect of the MEK inhibitor trametinib on cardiac repolarization in patients with solid tumours.
    Cancer chemotherapy and pharmacology, 2016, Volume: 78, Issue:3

    Trametinib is a reversible, selective inhibitor of the mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and 2 (MEK2). Cardiotoxicity (congestive heart failure, decreased heart rate, left ventricular dysfunction, and hypertension) related to trametinib is an infrequent, but serious, adverse event (AE). Prolongation of the QT interval increases the risk of life-threatening cardiac arrhythmia. Thus, the risk of trametinib inducing QT prolongation at putative supratherapeutic exposure was evaluated.. Eligible patients with solid tumours received placebo on day 1, once-daily trametinib 2-mg doses on days 2-14, and a single trametinib 3-mg dose on day 15 to achieve supratherapeutic dosing for QTc measurement. Electrocardiogram was assessed by 12-lead ambulatory 24-h Holter monitoring pre-dose, and on day 1 and day 15. Pharmacokinetic (PK) and pharmacodynamics (PD) parameters were measured.. Thirty-two of 35 patients completed the study. There was no effect of trametinib when compared with time-matched placebo on the change from baseline in QTcF, QTcB, or QTcI interval. Mean AUC0-24 and C max following trametinib 2-mg repeat doses were 364 ng.h/mL and 22.9 ng/mL, respectively; the corresponding values for the 3-mg dose were 454 ng.h/mL and 29.2 ng/mL. Median T max was approximately 2 h for both doses. Statistical analysis and PK/PD modelling showed no significant relationship between QTcF interval and trametinib plasma concentrations. AEs were consistent with those reported previously. No electrocardiogram abnormalities were reported as AEs.. The results of this study suggest trametinib has no significant effect on QT prolongation at supratherapeutic exposure.

    Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Area Under Curve; Cardiotoxicity; Electrocardiography; Electrocardiography, Ambulatory; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Models, Biological; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Single-Blind Method; Young Adult

2016
A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors.
    Investigational new drugs, 2016, Volume: 34, Issue:6

    Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease >16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.

    Topics: Adult; Aged; Biomarkers, Tumor; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; MAP Kinase Kinase 1; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Prognosis; Protein Kinase Inhibitors; Pyridazines; Pyridones; Pyrimidinones; Quinolines; Sulfonamides; Survival Rate; Tissue Distribution; TOR Serine-Threonine Kinases; Young Adult

2016
Cutaneous adverse events in patients treated with BRAF inhibitor-based therapies for metastatic melanoma for longer than 52 weeks.
    The British journal of dermatology, 2015, Volume: 172, Issue:1

    BRAF inhibitor-based therapies have been shown to induce cutaneous toxicities, with onset generally in the first 8-26 weeks of therapy.. To determine whether cutaneous toxicities persist in patients who have remained on BRAF inhibitor-based therapies for longer than 52 weeks, and therefore whether ongoing dermatology assessment is required.. All patients treated with the BRAF inhibitors vemurafenib or dabrafenib or combination BRAF inhibitor and mitogen-activated protein kinase kinase (MEK) inhibitor therapy at Westmead Hospital, Sydney, Australia underwent regular dermatological assessments for the duration of therapy. All patients enrolled in a clinical trial, and 18% of patients in the compassionate access scheme underwent a baseline assessment prior to commencement of therapy and every 4-8 weeks thereafter. Patients' adverse events were recorded in a specific database.. Patients continued to develop cutaneous adverse events after 52 weeks of continuous therapy. Patients on single-agent BRAF inhibitor therapy suffered from Grover disease (45%), plantar hyperkeratosis (45%), verrucal keratosis (18%) and even cutaneous squamous cell carcinoma (16%). The most frequent adverse event seen in patients in the combination BRAF and MEK inhibitor group was an acneiform eruption (40%).. Patients on BRAF inhibitor-based therapies need to continue to have regular dermatological follow-up independent of the duration of their therapy.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Eruptions; Female; Humans; Imidazoles; Indoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Neoplasm Metastasis; Oximes; Prospective Studies; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

2015
A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2015, Volume: 26, Issue:1

    This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity.. A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle.. Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%).. This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Everolimus; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

2015
Improved overall survival in melanoma with combined dabrafenib and trametinib.
    The New England journal of medicine, 2015, Jan-01, Volume: 372, Issue:1

    The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients.. In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival.. At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group.. Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Indoles; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Survival Analysis; Vemurafenib; Young Adult

2015
Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2015, Volume: 26, Issue:2

    Pyrexia is a frequent adverse event with combined dabrafenib and trametinib therapy (CombiDT), but little is known of its clinical associations, etiology, or appropriate management.. All patients on the BRF133220 phase I/II trial of CombiDT treated at the standard dose (150/2) were included for assessment of pyrexia (n = 201). BRAF and MEK inhibitor-naïve patients (n = 117) were included for efficacy analyses. Pyrexia was defined as temperature ≥38°C (≥100.4(°)F) or related symptoms.. Fifty-nine percent of patients developed pyrexia during treatment, 24% of which had pyrexia symptoms without a recorded elevation in body temperature. Pyrexia was grade 2+ in 60% of pyrexia patients. Median time to onset of first pyrexia was 19 days, with a median duration of 9 days. Pyrexia patients had a median of two pyrexia events, but 21% had three or more events. Various pyrexia management approaches were conducted in this study. A trend was observed between dabrafenib and hydroxy-dabrafenib exposure and pyrexia. No baseline clinical characteristics predicted pyrexia, and pyrexia was not statistically significantly associated with treatment outcome.. Pyrexia is a frequent and recurrent toxicity with CombiDT treatment. No baseline features predict pyrexia, and it is not associated with clinical outcome. Dabrafenib and metabolite exposure may contribute to the etiology of pyrexia. The optimal secondary prophylaxis for pyrexia is best studied in a prospective trial.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fever; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2015
Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma.
    Cancer chemotherapy and pharmacology, 2015, Volume: 75, Issue:1

    To identify the maximum tolerated dose (MTD) and recommended Phase II dose of MEK/AKT inhibitor combination of trametinib and afuresertib.. Eligibility criteria were advanced solid tumors, 18 years or older, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Exclusion criteria included Type 1 diabetes, active GI disease, leptomeningeal disease, or current evidence/risk of retinal venous occlusion/central serous retinopathy. Clinical safety parameters and response were evaluated and analyzed.. Twenty patients were enrolled. Dose-limiting toxicities (Grade 2 esophagitis; Grade 3 aspartate aminotransferase increased, mucosal inflammation and hypokalemia) were reported at starting dose (1.5 mg trametinib/50 mg afuresertib once daily continuously), exceeding the MTD. Subsequent de-escalation cohorts (1.5 mg/25 mg or 1.0 mg/50 mg trametinib/afuresertib) were defined as MTDs for continuous dosing. Intermittent dosing schedule [1.5 mg trametinib (continuous)/50 mg afuresertib (Days 1-10 every 28 days)] was evaluated and considered tolerable. No patients were enrolled in Phase II. The most common adverse events reported (≥10 % of all patients) included: diarrhea (60 %), dermatitis acneiform (55 %), maculo-papular rash (45 %), fatigue (30 %), dry skin (25 %), nausea (25 %), dyspnea (20 %), and vomiting (20 %). One partial response (BRAF wild-type melanoma) was reported; four patients had stable disease as best response.. Continuous daily dosing of trametinib/afuresertib combination was poorly tolerated. Evaluation of intermittent dose schedule showed greater tolerability. Given the interest in combination treatment regimens of MAPK and PI3K/AKT pathway inhibitors, further study of intermittent dose schedule or combination of trametinib with more selective inhibitors may be warranted.

    Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Dose-Response Relationship, Drug; Early Termination of Clinical Trials; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Multiple Myeloma; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyridones; Pyrimidinones; Thiophenes; Tumor Burden

2015
BRAF inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia and exert potent antileukemic activity.
    Blood, 2015, Feb-19, Volume: 125, Issue:8

    Hairy cell leukemia (HCL) shows unique clinicopathological and biological features. HCL responds well to purine analogs but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (vemurafenib; dabrafenib) or MEK (trametinib) inhibitors. Results were validated in vivo in samples from vemurafenib-treated HCL patients within a phase 2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, tartrate-resistant acid phosphatase, and cyclin D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by coculture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL.

    Topics: Antineoplastic Agents; Gene Expression Regulation, Leukemic; Humans; Imidazoles; Indoles; Leukemia, Hairy Cell; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Oximes; Phosphorylation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Transcriptome; Tumor Cells, Cultured; Vemurafenib

2015
A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2015, Feb-15, Volume: 21, Issue:4

    MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated.. This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non-small cell lung, ovarian, or pancreatic cancer.. Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non-small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination.. At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity.

    Topics: Adult; Aged; Aged, 80 and over; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Morpholines; Neoplasms; Pyridones; Pyrimidinones

2015
PACMEL: a phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel.
    European journal of cancer (Oxford, England : 1990), 2015, Volume: 51, Issue:3

    We sought to determine the maximal tolerated dose of the MEK inhibitor trametinib with weekly paclitaxel, with a view to exploring the combination's activity in melanoma lacking a BRAF V600 mutation.. In this phase 1 study we used a fixed dose of paclitaxel (80 mg/m2 intravenous (IV) on days 1, 8 and 15 of each 4 week cycle) and escalated the dose of trametinib (to a maximum 2mg orally (PO) daily), following a 3+3 design. Eligible patients had advanced melanoma and could have received up to two previous lines of treatment for metastatic disease.. 15 patients were enrolled, all but one of whose melanoma was wild type for BRAF at codon 600. The maximal monotherapy dose of trametinib proved tolerable with weekly paclitaxel. The most frequent adverse events observed were rash and fatigue. Six (40%) partial responses were reported, including four of eight patients with NRAS mutations. Median progression free survival was 5.5 months (95% confidence interval (CI) 1.8-7.8 months) and overall survival, 14.1 months (95% CI 4.6-not reached).. Trametinib can safely be given with weekly paclitaxel at the full monotherapy dose. In this small group promising progression free and overall survival were observed in patients with melanoma lacking a V600 BRAF mutation.

    Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Maximum Tolerated Dose; Melanoma; Middle Aged; Paclitaxel; Pyridones; Pyrimidinones; Skin Neoplasms

2015
A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2015, Volume: 26, Issue:5

    KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC.. Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m(2) i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary.. One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75-1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52-1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia.. Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC.. NCT01362296.

    Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Disease Progression; Disease-Free Survival; Docetaxel; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Signal Transduction; Taxoids; Time Factors; Treatment Outcome

2015
Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma.
    European journal of cancer (Oxford, England : 1990), 2015, Volume: 51, Issue:7

    To present the impact of treatments on health-related quality of life (HRQoL) from the double-blind, randomised phase III COMBI-d study that investigated the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600E/K-mutant metastatic melanoma. COMBI-d showed significantly prolonged progression-free survival for the combination.. HRQoL was evaluated using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, a generic cancer questionnaire (completed at baseline, during study treatment, at progression and post progression) assessing various dimensions (global health/QoL, functional status, and symptom impact). A mixed-model, repeated-measures analyses of covariance evaluated differences between arms.. Questionnaire completion rates were >95% at baseline, >85% to week 40 and >70% at disease progression. Baseline scores across both arms were comparable for all dimensions. Global health dimension scores were significantly better at weeks 8, 16 and 24 for patients receiving the combination during treatment and at progression. The majority of functional dimension scores (physical, social, role, emotional and cognitive functioning) trended in favour of the combination. Pain scores were significantly improved and clinically meaningful (6-13 point difference) for patients receiving the combination for all follow-up assessments versus those receiving dabrafenib monotherapy. For other symptom dimensions (nausea and vomiting, diarrhoea, dyspnoea, and constipation), scores trended in favour of dabrafenib monotherapy.. This analysis demonstrates that the combination of dabrafenib and trametinib provides better preservation of HRQoL and pain improvements versus dabrafenib monotherapy while also delaying progression. (Clinicaltrials.gov registration number: NCT01584648).

    Topics: Amino Acid Substitution; Antineoplastic Combined Chemotherapy Protocols; Health Status; Humans; Imidazoles; Melanoma; Neoplasm Metastasis; Oximes; Pain Measurement; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life; Skin Neoplasms; Valine

2015
Preliminary results from a prospective trial of preoperative combined BRAF and MEK-targeted therapy in advanced BRAF mutation-positive melanoma.
    Journal of the American College of Surgeons, 2015, Volume: 220, Issue:4

    We conducted a prospective trial of BRAF and mitogen-activated protein kinase kinase (MEK) targeted therapy in advanced, operable BRAF mutation-positive melanoma to determine feasibility, tumor response rates, and biomarkers of response and resistance.. Thirteen patients with locally or regionally advanced BRAF mutation-positive melanoma received dabrafenib 150 mg po bid for 14 days, followed by dabrafenib plus trametinib 2 mg po daily for 14 days before operation. Biopsies and tumor measurements were obtained at baseline and days 14 and 28. Formalin-fixed paraffin embedded specimens were analyzed with hematoxylin and eosin, Ki-67, cleaved caspase-3, CD8, phosphorylated extracellular signal-regulated kinase (ERK), and phosphorylated MEK immunostains.. Therapy was tolerated well, with toxicity ≥ grade 3 in 2 of 13 (15%) patients. All 12 patients receiving >14 days of therapy had substantial reduction in tumor volume (65% at day 14 and 78% at day 28) and underwent resection. After 14 days of dabrafenib therapy, there was a marked reduction in viable melanoma cells and a CD8 T-cell--rich infiltrate. Proliferation of the residual melanoma cells was reduced and apoptosis was increased. The cells continued to express phosphorylated ERK and phosphorylated MEK consistent with incomplete mitogen-activated protein kinase pathway inhibition.. Preoperative targeted therapy of advanced BRAF-mutant melanoma is feasible, well tolerated, induces brisk tumor responses, and facilitates correlative science. A CD8 T-cell-rich infiltrate indicates a potential immune-mediated mechanism of action. Both proliferation and apoptosis were inhibited, but the mitogen-activated protein kinase pathway remained activated, suggesting intrinsic resistance in a subset of tumor cells. Additional investigation of the anti-tumor immune response during targeted therapy and the mechanisms of intrinsic resistance can yield novel therapeutic strategies.

    Topics: Administration, Oral; Adult; Aged; Biomarkers, Tumor; Biopsy; DNA Mutational Analysis; DNA, Neoplasm; Dose-Response Relationship, Drug; Drug Therapy, Combination; Feasibility Studies; Female; Follow-Up Studies; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Oximes; Preoperative Care; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Young Adult

2015
Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial.
    Lancet (London, England), 2015, Aug-01, Volume: 386, Issue:9992

    Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article.. We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648.. Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25·1 months (95% CI 19·2-not reached) in the dabrafenib and trametinib group versus 18·7 months (15·2-23·7) in the dabrafenib only group (hazard ratio [HR] 0·71, 95% CI 0·55-0·92; p=0·0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11·0 months (95% CI 8·0-13·9) in the dabrafenib and trametinib group and 8·8 months (5·9-9·3) in the dabrafenib only group (HR 0·67, 95% CI 0·53-0·84; p=0·0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group.. The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing.. GlaxoSmithKline.

    Topics: Adult; Aged; Aged, 80 and over; Disease-Free Survival; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome; Young Adult

2015
A phase I/Ib study of trametinib (GSK1120212) alone and in combination with gemcitabine in Japanese patients with advanced solid tumors.
    Investigational new drugs, 2015, Volume: 33, Issue:5

    Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single-agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results.. In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m(2)).. In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2).. Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.).

    Topics: Adult; Aged; Antineoplastic Agents; Area Under Curve; Asian People; Deoxycytidine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gemcitabine; Humans; Japan; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pancreatic Neoplasms; Pyridones; Pyrimidinones

2015
MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia.
    Blood, 2015, Nov-05, Volume: 126, Issue:19

    The outcome for pediatric acute lymphoblastic leukemia (ALL) patients who relapse is dismal. A hallmark of relapsed disease is acquired resistance to multiple chemotherapeutic agents, particularly glucocorticoids. In this study, we performed a genome-scale short hairpin RNA screen to identify mediators of prednisolone sensitivity in ALL cell lines. The incorporation of these data with an integrated analysis of relapse-specific genetic and epigenetic changes allowed us to identify the mitogen-activated protein kinase (MAPK) pathway as a mediator of prednisolone resistance in pediatric ALL. We show that knockdown of the specific MAPK pathway members MEK2 and MEK4 increased sensitivity to prednisolone through distinct mechanisms. MEK4 knockdown increased sensitivity specifically to prednisolone by increasing the levels of the glucocorticoid receptor. MEK2 knockdown increased sensitivity to all chemotherapy agents tested by increasing the levels of p53. Furthermore, we demonstrate that inhibition of MEK1/2 with trametinib increased sensitivity of ALL cells and primary samples to chemotherapy in vitro and in vivo. To confirm a role for MAPK signaling in patients with relapsed ALL, we measured the activation of the MEK1/2 target ERK in matched diagnosis-relapse primary samples and observed increased phosphorylated ERK levels at relapse. Furthermore, relapse samples have an enhanced response to MEK inhibition compared to matched diagnosis samples in xenograft models. Together, our data indicate that inhibition of the MAPK pathway increases chemosensitivity to glucocorticoids and possibly other agents and that the MAPK pathway is an attractive target for prevention and/or treatment of relapsed disease.

    Topics: Adolescent; Animals; Cell Line, Tumor; Child; Child, Preschool; Drug Resistance, Neoplasm; Female; Gene Knockdown Techniques; Genome-Wide Association Study; Humans; Male; MAP Kinase Kinase 2; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mice; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisolone; Pyridones; Pyrimidinones; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

2015
A cost-effectiveness analysis of trametinib plus dabrafenib as first-line therapy for metastatic BRAF V600-mutated melanoma in the Swiss setting.
    The British journal of dermatology, 2015, Volume: 173, Issue:6

    The treatment of patients with metastatic melanomas that harbour BRAF V600E or V600K mutations with trametinib plus dabrafenib appears to be superior to treatment with vemurafenib alone. This treatment regimen is likely to become available in Switzerland in the near future.. To determine the cost-effectiveness of trametinib plus dabrafenib.. A Markov cohort simulation was conducted to model the clinical course of typical patients with metastatic melanoma. Information on response rates, clinical condition and follow-up treatments were derived and transition probabilities estimated based on the results of a clinical trial that compared treatment with trametinib plus dabrafenib vs. vemurafenib alone.. Treatment with trametinib plus dabrafenib was estimated to cost an additional CHF199 647 (Swiss francs) on average and yield a gain of 0·52 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio of CHF385 603 per QALY. Probabilistic sensitivity analyses showed that a willingness-to-pay threshold of CHF100 000 per QALY would not be reached at the current US price of trametinib.. The introduction of trametinib in Switzerland at US market prices for the treatment of metastatic BRAF V600-mutated melanoma with trametinib plus dabrafenib is unlikely to be cost-effective compared with vemurafenib monotherapy. A reduction in the total price of the combination therapy is required to achieve an acceptable cost-effectiveness ratio for this clinically promising treatment.

    Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Disease Progression; Drug Administration Schedule; Drug Costs; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life; Quality-Adjusted Life Years; Skin Neoplasms; Switzerland; Treatment Outcome

2015
Adjusting for confounding effects of treatment switching in a randomized phase II study of dabrafenib plus trametinib in BRAF V600+ metastatic melanoma.
    Melanoma research, 2015, Volume: 25, Issue:6

    Patients with BRAF V600E mutation-positive melanoma who were assigned to 150 mg dabrafenib twice daily combined with 2 mg trametinib once daily in a phase I/II study showed a median overall survival (OS) of 23.8 months, compared with 20.2 months for patients assigned to dabrafenib alone [hazard ratio (HR)=0.73, 95% confidence interval (CI) 0.43-1.24; data cutoff March 2013], on the basis of an intention-to-treat analysis. Because patients assigned to dabrafenib monotherapy were allowed to switch to combination therapy upon disease progression, we attempted to adjust for confounding effects on OS. Randomization-based adjustment methods, Rank Preserving Structural Failure Time Models and the Iterative Parameter Estimation algorithm, were used. Two analyses, 'treatment group' (assumes that treatment effect continues beyond treatment discontinuation) and 'on treatment' (assumes that the treatment effect disappears upon treatment discontinuation), were used to test assumptions on the durability of the treatment effect. A total of 45/54 (83%) patients assigned to dabrafenib monotherapy switched to the trametinib/dabrafenib combination. Adjusted OS HRs ranged from 0.47 to 0.50, depending on the analysis, compared with the unadjusted OS HR of 0.73. CIs continued to cross 1.00; thus, adjusted estimates did not provide statistically significant evidence of a treatment benefit on survival. Reduction of HRs after adjusting for the effect of treatment switching suggests that the intention-to-treat analysis underestimates the effect of dabrafenib plus trametinib on OS, although several factors, such as small trial size and methodological assumptions, affect the certainty of the conclusions.

    Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Substitution; Humans; Imidazoles; Kaplan-Meier Estimate; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2015
Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015, Dec-01, Volume: 33, Issue:34

    To evaluate dabrafenib, a selective BRAF inhibitor, combined with trametinib, a selective MEK inhibitor, in patients with BRAF V600-mutant metastatic colorectal cancer (mCRC).. A total of 43 patients with BRAF V600-mutant mCRC were treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily), 17 of whom were enrolled onto a pharmacodynamic cohort undergoing mandatory biopsies before and during treatment. Archival tissues were analyzed for microsatellite instability, PTEN status, and 487-gene sequencing. Patient-derived xenografts were established from core biopsy samples.. Of 43 patients, five (12%) achieved a partial response or better, including one (2%) complete response, with duration of response > 36 months; 24 patients (56%) achieved stable disease as best confirmed response. Ten patients (23%) remained in the study > 6 months. All nine evaluable during-treatment biopsies had reduced levels of phosphorylated ERK relative to pretreatment biopsies (average decrease ± standard deviation, 47% ± 24%). Mutational analysis revealed that the patient achieving a complete response and two of three evaluable patients achieving a partial response had PIK3CA mutations. Neither PTEN loss nor microsatellite instability correlated with efficacy. Responses to dabrafenib plus trametinib were comparable in patient-derived xenograft-bearing mice and the biopsied lesions from each corresponding patient.. The combination of dabrafenib plus trametinib has activity in a subset of patients with BRAF V600-mutant mCRC. Mitogen-activated protein kinase signaling was inhibited in all patients evaluated, but to a lesser degree than observed in BRAF-mutant melanoma with dabrafenib alone. PIK3CA mutations were identified in responding patients and thus do not preclude response to this regimen. Additional studies targeting the mitogen-activated protein kinase pathway in this disease are warranted.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Cohort Studies; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Mice; Microsatellite Instability; Middle Aged; Mutation; Neoplasm Staging; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; PTEN Phosphohydrolase; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2015
Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-l
    The Lancet. Oncology, 2015, Volume: 16, Issue:13

    In the COMBI-v trial, patients with previously untreated BRAF Val600Glu or Val600Lys mutant unresectable or metastatic melanoma who were treated with the combination of dabrafenib and trametinib had significantly longer overall and progression-free survival than those treated with vemurafenib alone. Here, we present the effects of treatments on health-related quality of life (HRQoL), an exploratory endpoint in the COMBI-v study.. COMBI-v was an open-label, randomised phase 3 study in which 704 patients with metastatic melanoma with a BRAF Val600 mutation were randomly assigned (1:1) by an interactive voice response system to receive either a combination of dabrafenib (150 mg twice-daily) and trametinib (2 mg once-daily) or vemurafenib monotherapy (960 mg twice-daily) orally as first-line therapy. The primary endpoint was overall survival. In this pre-specified exploratory analysis, we prospectively assessed HRQoL in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer quality of life (EORTC QLQ-C30), EuroQoL-5D (EQ-5D), and Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-M), completed at baseline, during study treatment, at disease progression, and after progression. We used a mixed-model, repeated measures ANCOVA to assess differences in mean scores between groups with baseline score as covariate; all p-values are descriptive. The COMBI-v trial is registered with ClinicalTrials.gov, number NCT01597908, and is ongoing for the primary endpoint, but is not recruiting patients.. From June 4, 2012, to Oct 7, 2013, 1645 patients at 193 centres worldwide were screened for eligibility, and 704 patients were randomly assigned to dabrafenib plus trametinib (n=352) or vemurafenib (n=352). Questionnaire completion rates for both groups were high (>95% at baseline, >80% at follow-up assessments, and >70% at disease progression) with similar HRQoL and symptom scores reported at baseline in both treatment groups for all questionnaires. Differences in mean scores between treatment groups were significant and clinically meaningful in favour of the combination compared with vemurafenib monotherapy for most domains across all three questionnaires during study treatment and at disease progression, including EORTC QLQ-C30 global health (7·92, 7·62, 6·86, 7·47, 5·16, 7·56, and 7·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·005 at week 40), EORTC QLQ-C30 pain (-13·20, -8·05, -8·82, -12·69, -12·46, -11·41, and -10·57 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001), EQ-5D thermometer scores (7·96, 8·05, 6·83, 11·53, 7·41, 9·08, and 10·51 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; p<0·001 for all assessments except p=0·006 at week 32), and FACT-M Melanoma Subscale score (3·62, 2·93, 2·45, 3·39, 2·85, 3·00, and 3·68 at weeks 8, 16, 24, 32, 40, 48, and disease progression, respectively; all p<0·001).. From the patient's perspective, which integrates not only survival advantage but also disease-associated and adverse-event-associated symptoms, treatment with the combination of a BRAF inhibitor plus a MEK inhibitor (dabrafenib plus trametinib) adds a clear benefit over monotherapy with the BRAF inhibitor vemurafenib and supports the combination therapy as standard of care in this population.

    Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Disease-Free Survival; DNA Mutational Analysis; Drug Administration Schedule; Genetic Predisposition to Disease; Humans; Imidazoles; Indoles; Intention to Treat Analysis; MAP Kinase Kinase Kinases; Melanoma; Mutation; Oximes; Phenotype; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life; Risk Factors; Skin Neoplasms; Sulfonamides; Surveys and Questionnaires; Time Factors; Treatment Outcome; Vemurafenib

2015
Granulomatous nephritis and dermatitis in a patient with BRAF V600E mutant metastatic melanoma treated with dabrafenib and trametinib.
    Melanoma research, 2015, Volume: 25, Issue:6

    A 61-year-old man was diagnosed with stage IIIB BRAF V600E mutant melanoma in October 2012. He was treated with a combination therapy of dabrafenib and trametinib. He remained in complete remission for 18 months and the treatment was well tolerated after dose reduction because of pyrexia. In March 2013, he developed bilateral pitting edema of the legs with an erythematous, slightly infiltrated rash on his back and upper arms. His face was edematous, with a heliotrope rash-like aspect. Eye examination showed bilateral blepharitis. Additional blood test showed inflammation and acute kidney injury Rifle category failure. A skin and kidney biopsy indicated a granulomatous inflammation. A complete workup for other causes of granulomatous inflammation was negative. Treatment with dabrafenib and trametinib was stopped and corticosteroids were initiated, with a rapid beneficial effect on both the kidney function and skin rash. When corticosteroids were halted after 1 month, a rapid decline in the kidney function was observed. After reintroduction of corticosteroids, kidney function normalized and steroids could be tapered gradually over 6 months. To our knowledge, interstitial nephritis has not been described in patients on BRAF-targeted nor MEK-targeted therapy for melanoma, although it has been described in a melanoma patient treated with the immune checkpoint inhibitor, ipilimumab. Currently, the patient has no sign of local or distal recurrence of melanoma, notwithstanding that treatment with dabrafenib and trametinib has been stopped for 10 months and no other antimelanoma therapy was initiated.

    Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Eruptions; Granuloma; Humans; Imidazoles; Male; Melanoma; Middle Aged; Nephritis, Interstitial; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2015
Relative bioavailability of pediatric oral solution and tablet formulations of trametinib in adult patients with solid tumors.
    Clinical pharmacology in drug development, 2015, Volume: 4, Issue:4

    Trametinib (Mekinist®) is a selective inhibitor of mitogen-activated protein kinase kinase (MEK) approved in the United States as a single agent and in combination with dabrafenib (Tafinlar®) for treatment of patients with unresectable or metastatic melanoma with a positive BRAF V600E/V600K mutation for which a pediatric oral solution formulation is being developed. This open-label, two-period, two-treatment, randomized, crossover study assessed the relative bioavailability of the trametinib pediatric oral solution compared to the tablet formulation after a single-dose administration to adult patients with solid tumors. Primary pharmacokinetic endpoints derived from standard non-compartmental methods were AUC0-inf , AUC0-t , and Cmax . As expected, Cmax was higher and Tmax earlier for the pediatric oral solution compared to the tablet formulation. Administration of the trametinib pediatric oral solution resulted in a 12%, 10%, 18%, and 71% higher AUC0-inf , AUC0-last , AUC0-24 , and Cmax , respectively, as compared to the tablet formulation. Safety results were aligned with the known safety profile of trametinib. No serious or non-serious adverse events resulted in study drug withdrawal. Palatability of the pediatric oral solution was evaluated and found to be acceptable to most adult patients, but may differ in the pediatric population.

    Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Biological Availability; Cross-Over Studies; Drug Compounding; Female; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Neoplasms; Patient Satisfaction; Pharmaceutical Solutions; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Tablets; Taste; United States

2015
Trametinib, a first-in-class oral MEK inhibitor mass balance study with limited enrollment of two male subjects with advanced cancers.
    Xenobiotica; the fate of foreign compounds in biological systems, 2014, Volume: 44, Issue:4

    1. This study assessed the mass balance, metabolism and disposition of [(14)C]trametinib, a first-in-class mitogen-activated extracellular signal-related kinase (MEK) inhibitor, as an open-label, single solution dose (2 mg, 2.9 MBq [79 µCi]) in two male subjects with advanced cancer. 2. Trametinib absorption was rapid. Excretion was primarily via feces (∼81% of excreted dose); minor route was urinary (∼19% of excreted dose). The primary metabolic elimination route was deacetylation alone or in combination with hydroxylation. Circulating drug-related component profiles (composed of parent with metabolites) were similar to those found in elimination together with N-glucuronide of deacetylation product. Metabolite analysis was only possible from <50% of administered dose; therefore, percent of excreted dose (defined as fraction of percent of administered dose recovery over total dose recovered in excreta) was used to assess the relative importance of excretion and metabolite routes. The long elimination half-life (∼10 days) favoring sustained targeted activity was important in permitting trametinib to be the first MEK inhibitor with clinical activity in late stage clinical studies. 3. This study exemplifies the challenges and adaptability needed to understand the metabolism and disposition of an anticancer agent, like trametinib, with both low exposure and a long elimination half-life.

    Topics: Absorption; Administration, Oral; Aged; Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Male; Melanoma; Middle Aged; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Radiometry; Radiopharmaceuticals; Rats; Skin Neoplasms

2014
MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition.
    Cancer discovery, 2014, Volume: 4, Issue:1

    Treatment of BRAF-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP-ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (MEK2(Q60P)). MEK2(Q60P) conferred resistance to combined RAF/MEK inhibition in vitro, but remained sensitive to inhibition of the downstream kinase extracellular signal-regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.

    Topics: Aged; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; raf Kinases; Signal Transduction; Skin Neoplasms

2014
Functional and symptom impact of trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-of-life analyses of the METRIC study.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2014, Volume: 25, Issue:3

    In a randomized phase III study, trametinib prolonged progression-free survival and improved overall survival versus chemotherapy in patients with BRAF V600 mutation-positive melanoma.. Patients' quality of life (QOL) was assessed at baseline and follow-up visits using the European Organisation for Research and Treatment of Cancer Core QOL questionnaire.. In the primary efficacy population (BRAF V600E+, no brain metastases) from baseline to weeks 6 and 12, patients' global health status scores worsened by 4-5 points with chemotherapy but improved by 2-3 points with trametinib. Rapid and substantive reductions in QOL functionality (e.g. role functioning, 8-11 points at weeks 6 and 12) and symptom exacerbation (e.g. fatigue, 4-8 points; nausea and vomiting, 5 points, both at weeks 6 and 12) were observed in chemotherapy-treated patients. In contrast, trametinib-treated patients reported small improvements or slight worsening from baseline at week 12, depending on the functional dimension and symptom. The mean symptom-scale scores for chemotherapy-treated patients increased from baseline (symptoms worsened) for seven of eight symptoms at week 6 (except insomnia) and six of eight symptoms at week 12 (except dyspnea and insomnia). In contrast, at weeks 6 and 12, the mean symptom-scale scores for trametinib decreased from baseline (symptoms improved) for pain (11-12 points), insomnia (10-12 points), and appetite loss (1-5 points), whereas those for diarrhea worsened (15-16 points). Mixed-model repeated-measures analyses showed significant (P < 0.05) and/or clinically meaningful improvements (small to moderate) from baseline in favor of trametinib for global health; physical, role, and social functioning; fatigue; pain; insomnia; nausea and vomiting; constipation; dyspnea; and appetite at weeks 6 and/or 12. QOL results for the intent-to-treat population were consistent.. This first QOL assessment for a MEK inhibitor in metastatic melanoma demonstrated that trametinib was associated with less functional impairment, smaller declines in health status, and less exacerbation of symptoms versus chemotherapy.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Disease-Free Survival; Health Status; Humans; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Paclitaxel; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life; Surveys and Questionnaires

2014
Concomitant oral and intravenous pharmacokinetics of trametinib, a MEK inhibitor, in subjects with solid tumours.
    British journal of clinical pharmacology, 2014, Volume: 78, Issue:3

    The aim of this phase 1, single centre, open label study in four patients with solid tumours was to determine the absolute bioavailability of a 2 mg oral dose of trametinib. Trametinib is an orally bioavailable, reversible and selective allosteric inhibitor of MEK1 and MEK2 activation and kinase activity.. A microtracer study approach, in which a 5 μg radiolabelled i.v. microdose of trametinib was given concomitantly with an unlabelled 2 mg oral tablet formulation, was used to recover i.v. and oral pharmacokinetic parameters, simultaneously.. The least-squares mean (90% confidence interval) absolute bioavailability of trametinib (2 mg tablet) was 72.3% (50.0%, 104.6%). Median tmax after oral administration was 1.5 h and the geometric mean terminal half-life was 11 days. The geometric mean clearance and volume of distribution after i.v. administration were 3.21 l h(-1) and 976 l, respectively, resulting in a terminal elimination half-life of 11 days.. Trametinib absolute bioavailability was moderate to high, whereas first pass metabolism was low.

    Topics: Administration, Intravenous; Administration, Oral; Antineoplastic Agents; Biological Availability; Female; Half-Life; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Tissue Distribution

2014
A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas.
    European journal of cancer (Oxford, England : 1990), 2014, Volume: 50, Issue:12

    Trametinib, an oral mitogen/extracellular signal-related kinase (MEK)1/2 inhibitor, holds promise for malignancies with rat sarcoma (RAS) mutations, like pancreas cancer. This phase II study was designed to determine overall survival (OS) in patients with pancreas cancer treated with trametinib and gemcitabine. Secondary end-points included progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR); safety end-points were also assessed.. Adults with untreated metastatic adenocarcinoma of the pancreas were randomised (1:1) to receive intravenous gemcitabine 1000 mg/m(2) (weekly × 7 for 8 weeks, then days 1, 8 and 15 of 28-day cycles) plus trametinib or placebo 2mg daily. RAS mutations were determined in circulating free DNA (cfDNA) and archival tumour tissue. OS was evaluated in kirsten rat sarcoma viral oncogene homolog (KRAS) mutant and wild-type subgroups.. Baseline characteristics for 160 patients were similar in both treatment arms. There was no significant difference in OS (hazard ratio (HR) 0.98; 95% confidence interval (CI), 0.67-1.44; P=.453); median OS was 8.4 months with gemcitabine plus trametinib and 6.7 months with gemcitabine plus placebo. Median PFS (16 versus 15 weeks), ORR (22% versus 18%) and median DOR (23.9 versus 16.1 weeks) were also similar for trametinib and placebo arms, respectively. KRAS mutation-positive patients (n=103) showed no difference in OS between arms. Thrombocytopenia, diarrhoea, rash and stomatitis were more frequent with trametinib, as was grade 3 anaemia.. The addition of trametinib to gemcitabine did not improve OS, PFS, ORR or DOR in patients with previously untreated metastatic pancreas cancer. Outcomes were independent of KRAS mutations determined by cfDNA.

    Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Double-Blind Method; Female; Gemcitabine; Humans; Male; Middle Aged; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Survival Analysis

2014
Clinical profiling of BCL-2 family members in the setting of BRAF inhibition offers a rationale for targeting de novo resistance using BH3 mimetics.
    PloS one, 2014, Volume: 9, Issue:7

    While response rates to BRAF inhibitiors (BRAFi) are high, disease progression emerges quickly. One strategy to delay the onset of resistance is to target anti-apoptotic proteins such as BCL-2, known to be associated with a poor prognosis. We analyzed BCL-2 family member expression levels of 34 samples from 17 patients collected before and 10 to 14 days after treatment initiation with either vemurafenib or dabrafenib/trametinib combination. The observed changes in mRNA and protein levels with BRAFi treatment led us to hypothesize that combining BRAFi with a BCL-2 inhibitor (the BH3-mimetic navitoclax) would improve outcome. We tested this hypothesis in cell lines and in mice. Pretreatment mRNA levels of BCL-2 negatively correlated with maximal tumor regression. Early increases in mRNA levels were seen in BIM, BCL-XL, BID and BCL2-W, as were decreases in MCL-1 and BCL2A. No significant changes were observed with BCL-2. Using reverse phase protein array (RPPA), significant increases in protein levels were found in BIM and BID. No changes in mRNA or protein correlated with response. Concurrent BRAF (PLX4720) and BCL2 (navitoclax) inhibition synergistically reduced viability in BRAF mutant cell lines and correlated with down-modulation of MCL-1 and BIM induction after PLX4720 treatment. In xenograft models, navitoclax enhanced the efficacy of PLX4720. The combination of a selective BRAF inhibitor with a BH3-mimetic promises to be an important therapeutic strategy capable of enhancing the clinical efficacy of BRAF inhibition in many patients that might otherwise succumb quickly to de novo resistance. Trial registrations: ClinicalTrials.gov NCT01006980; ClinicalTrials.gov NCT01107418; ClinicalTrials.gov NCT01264380; ClinicalTrials.gov NCT01248936; ClinicalTrials.gov NCT00949702; ClinicalTrials.gov NCT01072175.

    Topics: Adult; Aged; Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Imidazoles; Indoles; Melanoma; Mice; Middle Aged; Mutation, Missense; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-bcl-2; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2014
Features and management of pyrexia with combined dabrafenib and trametinib in metastatic melanoma.
    Melanoma research, 2014, Volume: 24, Issue:5

    The combination of dabrafenib and trametinib (CombiDT) is an effective treatment for BRAF-mutant metastatic melanoma; however, over 70% of patients develop drug-related pyrexia, and little is known about this toxicity. We sought to examine the features and management of CombiDT pyrexia. The association between pyrexia and patient demographics, disease characteristics and outcome variables was assessed in patients treated with CombiDT at a single institution. The clinicopathological features of pyrexic events were analysed. Fourteen of 32 (44%) patients developed pyrexia (temperature≥38.5°C). Pyrexia was recurrent in 11/14 (79%). The median time to pyrexia was 38 days. Pyrexia was not associated with age, sex nor disease burden, and did not correlate with RECIST response, progression-free nor overall survival. Paracetamol, NSAIDs and/or dose reduction (DR) were ineffective secondary prophylaxis for pyrexia, whereas corticosteroids were effective in all patients (n=8), including two with multiple previous pyrexic events despite several DRs. In patients with previous DRs who commenced steroids (n=3), CombiDT doses were re-escalated without pyrexia. Pyrexia is a frequent and recurrent toxicity with CombiDT, with no predictive clinical characteristics. Pyrexia does not correlate with clinical outcome. Neither DR nor antipyretics are effective secondary prophylaxis, whereas corticosteroids are effective, prevent DR and enable re-escalation of CombiDT dosing.

    Topics: Acetaminophen; Adrenal Cortex Hormones; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Fever; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Temperature; Treatment Outcome

2014
Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.
    The New England journal of medicine, 2014, Nov-13, Volume: 371, Issue:20

    Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations.. In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted.. The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group.. A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648.).

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Double-Blind Method; Female; Fever; Humans; Imidazoles; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2014
Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2014, Nov-20, Volume: 32, Issue:33

    Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAF(V600)-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment.. In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45).. In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%).. Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor-resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2014
A phase 1b study of trametinib, an oral Mitogen-activated protein kinase kinase (MEK) inhibitor, in combination with gemcitabine in advanced solid tumours.
    European journal of cancer (Oxford, England : 1990), 2013, Volume: 49, Issue:9

    This phase 1b study determined the safety, tolerability, and recommended phase 2 dose (RP2D) and schedule of trametinib in combination with gemcitabine. Secondary objectives included assessment of clinical activity and steady-state pharmacokinetics.. Adults with advanced solid tumours, adequate organ function and Eastern Co-operative Oncology Group performance status (ECOG PS) ⩽ 1 were eligible. Once-daily oral trametinib (1mg, 2mg, 2.5mg) was escalated in a 3+3 design with standard gemcitabine dosing (1000 mg/m(2) IV Days 1, 8, and 15 of 28-day cycles). During expansion, trametinib 2mg was combined with gemcitabine. Pharmacokinetics samples were collected on Day 15 pre-dose and 1, 2, 4 and 6h post-dose; tumour assessments were repeated every two cycles.. Between 8/2009 and 11/2010, 31 patients (pancreas = 11, breast = 6, non-small cell lung cancer (NSCLC) = 4, other = 10) were treated. Dose-limiting toxicities (DLTs) occurred in each cohort, and included febrile neutropenia, transaminase elevation and uveitis. The RP2D was declared as trametinib 2mg daily with standard gemcitabine dosing. Common grade 3/4 toxicities at the RP2D included: neutropenia (38%), thrombocytopenia (19%) and transaminase elevation (14%). Of 10 patients with measurable pancreatic cancer, three partial responses (30%) were documented; two additional patients achieved objective responses (breast, complete response (CR); salivary glands, partial response (PR)). Pharmacokinetics suggested no change in exposures of either drug in combination.. Administration of trametinib at its full monotherapy dose of 2mg daily in combination with standard gemcitabine dosing (1000 mg/m(2) IV Days 1, 8, and 15 every 28 days) was feasible. Though most toxicities were manageable, the addition of trametinib may increase gemcitabine-associated myelosuppression. Future studies of this combination will require monitoring to maintain dose and schedule.

    Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Pyridones; Pyrimidinones; Thrombocytopenia; Treatment Outcome

2013
Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma.
    Molecular cancer therapeutics, 2013, Volume: 12, Issue:7

    Inhibitors of the mitogen-activated protein kinases (MAPK), BRAF, and MAP-ERK kinase (MEK) induce tumor regression in the majority of patients with BRAF-mutant metastatic melanoma. The clinical benefit of MAPK inhibitors is restricted by the development of acquired resistance with half of those who benefit having progressed by 6 to 7 months and long-term responders uncommon. There remains no agreed treatment strategy on disease progression in these patients. Without published evidence, fears of accelerated disease progression on inhibitor withdrawal have led to the continuation of drugs beyond formal disease progression. We now show that treatment with MAPK inhibitors beyond disease progression can provide significant clinical benefit, and the withdrawal of these inhibitors led to a marked increase in the rate of disease progression in two patients. We also show that MAPK inhibitors retain partial activity in acquired resistant melanoma by examining drug-resistant clones generated to dabrafenib, trametinib, or the combination of these drugs. All resistant sublines displayed a markedly slower rate of proliferation when exposed to MAPK inhibitors, and this coincided with a reduction in MAPK signaling, decrease in bromodeoxyuridine incorporation, and S-phase inhibition. This cytostatic effect was also associated with diminished levels of cyclin D1 and p-pRb. Two short-term melanoma cultures generated from resistant tumor biopsies also responded to MAPK inhibition, with comparable inhibitory changes in proliferation and MAPK signaling. These data provide a rationale for the continuation of BRAF and MEK inhibitors after disease progression and support the development of clinical trials to examine this strategy.

    Topics: Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2013
Evaluation of the effects of food on the single-dose pharmacokinetics of trametinib, a first-in-class MEK inhibitor, in patients with cancer.
    Journal of clinical pharmacology, 2013, Volume: 53, Issue:9

    The aim of this study was to estimate the effect of a high-fat, high-calorie meal on the single-dose pharmacokinetics (PK) of trametinib, a MEK inhibitor. The design of this 2 treatment, 2 period crossover, incomplete wash-out study was influenced by the subject population, long half-life and PK variability; 24 subjects were randomized to a single, oral 2 mg trametinib dose administered in a fed/fasted state, followed by 7 days of serial PK sampling. Period 2 PK parameters were adjusted based on residual Period 1 concentrations. Geometric least square mean ratios of fed:fasted were 0.30, 0.76, and 0.90 for corrected maximum concentration (C(max)), area under concentration-time curve from time 0 to last quantifiable sample (AUC(0-last)) and AUC from time 0 extrapolated to infinity (AUC(0-α)), respectively. Median half-life was 6.3 and 5.3 days for fed and fasted regimens, respectively. Uncorrected PK parameters were consistent with these results. Food delayed absorption and had a mean difference in time of maximum concentration (t(max)) of 3.9 hours. Both oral trametinib doses were well-tolerated. Single-dose trametinib administration with food decreased the rate and, to a lesser degree, the extent of absorption, supporting the recommendation to administer trametinib 1 hour before or 2 hours after a meal.

    Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Cross-Over Studies; Diet, High-Fat; Fasting; Female; Food-Drug Interactions; Half-Life; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2013
Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2013, Feb-01, Volume: 31, Issue:4

    BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAF-mutant melanoma.. This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily.. In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed.. Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor-naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.

    Topics: Adult; Aged; Antineoplastic Agents; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2013
Improved survival with MEK inhibition in BRAF-mutated melanoma.
    The New England journal of medicine, 2012, Jul-12, Volume: 367, Issue:2

    Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population.. In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point.. Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P=0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed.. Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Female; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Middle Aged; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

2012
Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial.
    The Lancet. Oncology, 2012, Volume: 13, Issue:8

    Inhibition of MEK stops cell proliferation and induces apoptosis; therefore, this enzyme is a key anticancer target. Trametinib is a selective, orally administered MEK1/MEK2 inhibitor. We aimed to define the maximum tolerated dose and recommended phase 2 dose of trametinib and to assess its safety, pharmacokinetics, pharmacodynamics, and response rate in individuals with advanced solid tumours.. We undertook a multicentre phase 1 study in patients with advanced solid tumours and adequate organ function. The study was in three parts: dose escalation to define the maximum tolerated dose; identification of the recommended phase 2 dose; and assessment of pharmacodynamic changes. Intermittent and continuous dosing regimens were analysed. Blood samples and tumour biopsy specimens were taken to assess pharmacokinetic and pharmacodynamic changes. Adverse events were defined with common toxicity criteria, and tumour response was measured by Response Evaluation Criteria In Solid Tumors. This study is registered with ClinicalTrials.gov, number NCT00687622.. We enrolled 206 patients (median age 58·5 years, range 19-92). Dose-limiting toxic effects included rash (n=2), diarrhoea (n=1), and central serous retinopathy (n=2). The most common treatment-related adverse events were rash or dermatitis acneiform (n=165; 80%) and diarrhoea (87; 42%), most of which were grade 1 and 2. The maximum tolerated dose was 3 mg once daily and the recommended phase 2 dose was 2 mg a day. The effective half-life of trametinib was about 4 days. At the recommended phase 2 dose, the exposure profile of the drug showed low interpatient variability and a small peak:trough ratio of 1·81. Furthermore, mean concentrations in plasma were greater than the preclinical target concentration throughout the dosing interval. Pathway inhibition and clinical activity were seen, with 21 (10%) objective responses recorded.. The recommended phase 2 dose of 2 mg trametinib once a day is tolerable, with manageable side-effects. Trametinib's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination.. GlaxoSmithKline.

    Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Area Under Curve; Biopsy; Drug Administration Schedule; Drug Monitoring; Female; Half-Life; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Maximum Tolerated Dose; Metabolic Clearance Rate; Middle Aged; Molecular Targeted Therapy; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Treatment Outcome; United States; Young Adult

2012
Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial.
    The Lancet. Oncology, 2012, Volume: 13, Issue:8

    MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma.. We undertook a multicentre, phase 1 three-part study (dose escalation, cohort expansion, and pharmacodynamic assessment). The main results of this study are reported elsewhere; here we present data relating to patients with melanoma. We obtained tumour samples to assess BRAF mutational status, and available tissues underwent exploratory genotyping analysis. Disease response was measured by Response Evaluation Criteria in Solid Tumors, and adverse events were defined by common toxicity criteria. This study is registered with ClinicalTrials.gov, number NCT00687622.. 97 patients with melanoma were enrolled, including 81 with cutaneous or unknown primary melanoma (36 BRAF mutant, 39 BRAF wild-type, six BRAF status unknown), and 16 with uveal melanoma. The most common treatment-related adverse events were rash or dermatitis acneiform (n=80; 82%) and diarrhoea (44; 45%), most of which were grade 2 or lower. No cutaneous squamous-cell carcinomas were recorded. Of 36 patients with BRAF mutations, 30 had not received a BRAF inhibitor before; two complete responses (both confirmed) and ten partial responses (eight confirmed) were noted in this subgroup (confirmed response rate, 33%). Median progression-free survival of this subgroup was 5·7 months (95% CI 4·0-7·4). Of the six patients who had received previous BRAF inhibition, one unconfirmed partial response was recorded. Of 39 patients with BRAF wild-type melanoma, four partial responses were confirmed (confirmed response rate, 10%).. Our data show substantial clinical activity of trametinib in melanoma and suggest that MEK is a valid therapeutic target. Differences in response rates according to mutations indicate the importance of mutational analyses in the future.. GlaxoSmithKline.

    Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Disease-Free Survival; DNA Mutational Analysis; Drug Administration Schedule; Female; Humans; Kaplan-Meier Estimate; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Time Factors; Treatment Outcome; United States; Uveal Neoplasms; Young Adult

2012
Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.
    The New England journal of medicine, 2012, 11-01, Volume: 367, Issue:18

    Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.. In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.. Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03).. Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Therapy, Combination; Female; Fever; Humans; Imidazoles; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2012

Other Studies

665 other study(ies) available for pyrimidinones and trametinib

ArticleYear
Trametinib for Painful Glomus Tumors in a Patient with Neurofibromatosis Type 1.
    The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 2023, Volume: 50, Issue:3

    Topics: Glomus Tumor; Humans; Neurofibromatosis 1; Pain; Pyridones; Pyrimidinones

2023
Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia.
    Blood, 2023, 03-02, Volume: 141, Issue:9

    BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation-positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Hairy Cell; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2023
Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy.
    Pediatric blood & cancer, 2023, Volume: 70, Issue:3

    The event-free survival of pediatric low-grade gliomas is poor, and patients often require multiple treatment strategies. While MEK and RAF inhibitors are efficacious in early-phase trials, not all patients respond, and many experience progression following completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. We report our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system tumors. Two of four patients using this combination therapy experienced severe thromboembolic events, necessitating discontinuation of therapy. This combination requires further investigation, and we urge caution if used.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Humans; Lenalidomide; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2023
In brief: A new indication for dabrafenib (Tafinlar) and trametinib (Mekinist) combination therapy.
    The Medical letter on drugs and therapeutics, 2023, 02-06, Volume: 65, Issue:1669

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2023
Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma.
    International journal of molecular sciences, 2023, Feb-24, Volume: 24, Issue:5

    Topics: Humans; Male; MAP Kinase Kinase 1; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2023
Real-life use of trametinib after immunotherapy failure in BRAF wild-type advanced melanoma.
    Melanoma research, 2023, 06-01, Volume: 33, Issue:3

    BRAF V600 wild-type advanced melanomas quickly reach a therapeutic dead-end, after immunotherapy failure. Even if preclinical studies have suggested sensitivity to MEK inhibitors such as trametinib in NRAS, NF1 or GNA mutated melanoma, therapeutic options are limited for these patients. We present a retrospective monocentric study of 22 patients with advanced melanoma treated by trametinib after immunotherapy resistance. Melanomas harboured NRAS (20), NF1 (1) or GNA 11 (1) mutations. For most of them (18), anti-PD1 was associated with trametinib. A disease-control was reported in 36% of patients (8/22), with six stable diseases and two partial responses according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Median progression-free survival was 2 months (1-14) and median overall survival was 6.5 months (2-24). In patients with progressive disease (14/22), dissociated radiologic responses and clinical benefits such as pain reduction were seen in five patients. High blood level of lactate dehydrogenase (LDH) seemed associated with trametinib failure, without significance ( P  = 0.06). Adverse events (grade 1-3) occurred in 91% of patients during the first weeks of treatment, mainly papulo-pustular rashes (77%), leg oedemas (36%), asthenia (18%) and diarrhoea (14%). This real-life study showed that trametinib may benefit some metastatic melanoma that progressed after chemotherapy and immune checkpoint inhibitors. Objective disease control (partial response or stable disease) using RECIST criteria was observed in 36% of patients. Because of frequent side-effects which can alter the quality of life and the short response duration, this off-label option has to be discussed with the patient. Studies with combination therapy with trametinib to improve relapse-free survival and lower side-effects are ongoing.

    Topics: Humans; Immunotherapy; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life; Retrospective Studies; Skin Neoplasms

2023
Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors.
    Cancer, 2023, 06-15, Volume: 129, Issue:12

    Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines.. Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones.. Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m. HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proteomics; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2023
Trametinib in Patients With
    JCO precision oncology, 2023, Volume: 7

    NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with. Eligible patients had tumors with deleterious inactivating. Fifty patients were eligible and started therapy: 46 with. Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

    Topics: GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Melanoma; Neurofibromatosis 1; Pyridones; Pyrimidinones

2023
Extemporaneous compounding of dabrafenib and trametinib for cancer patients with feeding tubes.
    Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 2023, Volume: 29, Issue:6

    Dabrafenib and trametinib are oral targeted agents indicated for BRAF mutated non-small cell lung cancer and melanoma. There is little data to support the administration of these two agents via enteral feeding tube. This case series describes three patients who received compounded dabrafenib and trametinib suspensions through enteral feeding tubes.. We present three patients who required dabrafenib and trametinib to be prepared as a non-standard compound for the medications to be administered via feeding tube. The patients were diagnosed with with BRAF mutated cancers including melanoma, non-small-cell lung carcinoma, and anaplastic thyroid cancer. In all three cases, there was evidence of initial disease response on imaging, and there were no unexpected toxicities secondary to dabrafenib and trametinib.. There are patients that are unable to tolerate medications by mouth due to dysphagia, anatomical malfunctions, or other digestive disorders. There is limited literature that describes preparation of trametinib and dabrafenib into an enteral suspension. Identifying a safe and efficacious method of administering these two medications via feeding tube ensures that these patients continue to be able to receive them as part of their anti-cancer therapy.. Despite the lack of available data, compounding of dabrafenib and trametinib may be clinically appropriate when benefits outweigh the risk of unconventional administration. Further studies are warranted to assess for the pharmacokinetics, pharmacodynamics, stability, and storage for these liquid medications.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyrimidinones

2023
Outcomes in patients with
    Tumori, 2023, Volume: 109, Issue:6

    Brain metastases (BM) and lactate dehydrogenase (LDH) levels above the upper limit of normal (ULN) are associated with poor prognosis in patients with melanoma. Although treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib have demonstrated long-term clinical benefit in patients with melanoma, data on their efficacy in patients with BM are limited.. DESCRIBE Italy is an observational, retrospective, real-world study evaluating dabrafenib plus trametinib in 499 patients with. Overall, 325 evaluable patients were on first-line therapy and are the focus of this analysis; of these, 76 patients (23.4%) had BM at baseline. mPFS was lower for patients with BM at baseline compared with overall patients (8.7 months vs 9.3 months, respectively). Patients with BM at diagnosis and LDH >ULN had a considerably shorter mPFS compared with patients with LDH ⩽ULN (5.3 months vs 9.9 months, respectively). mPFS was noticeably longer for patients with cerebral metastases only compared with patients with cerebral and other metastases (15.0 months vs 8.7 months, respectively).. Dabrafenib plus trametinib showed effectiveness in a real-world population of patients with advanced

    Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

2023
Vitiligo-like hypopigmentation induced by dabrafenib-trametinib: a potential marker for clinical response.
    Melanoma research, 2023, 12-01, Volume: 33, Issue:6

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vitiligo

2023
DA-Raf and the MEK inhibitor trametinib reverse skeletal myocyte differentiation inhibition or muscle atrophy caused by myostatin and GDF11 through the non-Smad Ras-ERK pathway.
    Journal of biochemistry, 2022, Jan-07, Volume: 171, Issue:1

    Myostatin (Mstn) and GDF11 are critical factors that are involved in muscle atrophy in the young and sarcopenia in the elderly, respectively. These TGF-β superfamily proteins activate not only Smad signalling but also non-Smad signalling including the Ras-mediated ERK pathway (Raf-MEK-ERK phosphorylation cascade). Although Mstn and GDF11 have been shown to induce muscle atrophy or sarcopenia by Smad2/3-mediated Akt inhibition, participation of the non-Smad Ras-ERK pathway in atrophy and sarcopenia has not been well determined. We show here that both Mstn and GDF11 prevented skeletal myocyte differentiation but that the MEK inhibitor U0126 or trametinib restored differentiation in Mstn- or GDF11-treated myocytes. These MEK inhibitors induced the expression of DA-Raf1 (DA-Raf), which is a dominant-negative antagonist of the Ras-ERK pathway. Exogenous expression of DA-Raf in Mstn- or GDF11-treated myocytes restored differentiation. Furthermore, administration of trametinib to aged mice resulted in an increase in myofiber size or recovery from muscle atrophy. The trametinib administration downregulated ERK activity in these muscles. These results imply that the Mstn/GDF11-induced Ras-ERK pathway plays critical roles in the inhibition of myocyte differentiation and muscle regeneration, which leads to muscle atrophy. Trametinib and similar approved drugs might be applicable to the treatment of muscle atrophy in sarcopenia or cachexia.

    Topics: Animals; Bone Morphogenetic Proteins; Growth Differentiation Factors; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Myostatin; Pyridones; Pyrimidinones

2022
KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation.
    European journal of cancer (Oxford, England : 1990), 2022, Volume: 160

    Parts 4 and 5 of the phase 1/2 KEYNOTE-022 study investigated the maximum tolerated dose (MTD), safety, and efficacy of pembrolizumab plus trametinib in solid tumours and BRAF wild-type melanoma.. Patients received intermittent or concurrent dosing of pembrolizumab plus trametinib. Concurrent dosing was 2 or 4 weeks of trametinib run-in followed by concurrent pembrolizumab every 3 weeks (Q3W) plus trametinib once daily (QD). Intermittent dosing was 2 weeks of trametinib run-in followed by pembrolizumab plus intermittent trametinib (1 week off/2 weeks on). A 3 + 3 dose escalation was used, followed by dose confirmation.. Forty-two patients were enrolled. No dose-limiting toxicities (DLTs) occurred at initial dose levels (DL). At subsequent DLs, 10 of 38 evaluable patients had DLTs. For concurrent dosing, MTD was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg QD, with a 2-week trametinib 1.5 mg QD run-in (concurrent DL2a); in concurrent DL2a group, five (31%) patients had grade 3/4 treatment-related adverse events (TRAEs); the objective response rate (ORR) was 0%. ORR was 40% in concurrent DL1 and 0% in concurrent DL2b. For intermittent dosing, MTD was pembrolizumab 200 mg Q3W plus trametinib 2 mg QD with a 2-week trametinib 2 mg QD run-in (intermittent DL2); in the intermittent DL2 group, seven (47%) patients had grade 3/4 TRAEs; ORR was 27%. ORR in intermittent DL1 was 33%.. MTDs for concurrent and intermittent dosing of pembrolizumab with trametinib were identified. The combination had limited antitumour activity, numerically higher ORR with intermittent versus concurrent dosing, and manageable safety. CLINICALTRIALS.. NCT02130466.

    Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Male; Melanoma; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2022
FGFR2 loss sensitizes MYCN-amplified neuroblastoma CHP134 cells to CHK1 inhibitor-induced apoptosis.
    Cancer science, 2022, Volume: 113, Issue:2

    Checkpoint kinase 1 (CHK1) plays a key role in genome surveillance and integrity throughout the cell cycle. Selective inhibitors of CHK1 (CHK1i) are undergoing clinical evaluation for various human malignancies, including neuroblastoma. In this study, one CHK1i-sensitive neuroblastoma cell line, CHP134, was investigated, which characteristically carries MYCN amplification and a chromosome deletion within the 10q region. Among several cancer-related genes in the chromosome 10q region, mRNA expression of fibroblast growth factor receptor 2 (FGFR2) was altered in CHP134 cells and associated with an unfavorable prognosis of patients with neuroblastoma. Induced expression of FGFR2 in CHP134 cells reactivated downstream MEK/ERK signaling and resulted in cells resistant to CHK1i-mediated cell growth inhibition. Consistently, the MEK1/2 inhibitor, trametinib, potentiated CHK1 inhibitor-mediated cell death in these cells. These results suggested that FGFR2 loss might be prone to highly effective CHK1i treatment. In conclusion, extreme cellular dependency of ERK activation may imply a possible application for the MEK1/2 inhibitor, either as a single inhibitor or in combination with CHK1i in MYCN-amplified neuroblastomas.

    Topics: Apoptosis; Cell Line, Tumor; Checkpoint Kinase 1; Drug Resistance, Neoplasm; Drug Synergism; Gene Amplification; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; N-Myc Proto-Oncogene Protein; Neuroblastoma; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptor, Fibroblast Growth Factor, Type 2; RNA, Messenger

2022
Combinatorial effects of azacitidine and trametinib on NRAS-mutated melanoma.
    Pediatric blood & cancer, 2022, Volume: 69, Issue:4

    Congenital melanocytic nevus (CMN) syndrome represents a mosaic RASopathy, typically caused by postzygotic NRAS codon 61 mutations, which originate in ectodermal precursor cells and result in melanocyte deposits in the skin and central nervous system (CNS). Affected patients are prone to develop uniformly fatal melanomas in the skin and CNS. Here, we report the case of a 2.7-year-old male with CMN syndrome, diffuse leptomeningeal melanosis and CNS melanoma, who underwent experimental therapy with the DNA methyltransferase inhibitor azacitidine in combination with the mitogen-activated protein kinase (MEK) inhibitor trametinib with exceptional clinical and radiological response. Response to combination therapy appeared to be more durable than the treatment response observed in several other severely affected patients treated with trametinib for late-stage disease. Correspondingly, concomitant exposure to trametinib and azacitidine prevented development of trametinib resistance in NRAS-mutated human melanoma cells in vitro. Also, azacitidine was shown to inhibit growth and mitogen-activated protein kinase 1/2 (ERK1/2) phosphorylation of melanoma cells and act synergistically with trametinib to inhibit the growth of trametinib-resistant melanoma cells. These observations suggest that azacitidine enhances trametinib monotherapy and may represent a promising candidate drug for combination therapies to enhance the efficacy of MEK inhibitors in RAS-driven diseases.

    Topics: Azacitidine; Child, Preschool; GTP Phosphohydrolases; Humans; Male; Melanoma; Membrane Proteins; Meningeal Neoplasms; Mitogen-Activated Protein Kinase Kinases; Mutation; Nevus, Pigmented; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

2022
Reply to: Letter comments on: Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers.
    European journal of cancer (Oxford, England : 1990), 2022, Volume: 162

    Topics: Fever; Humans; Imidazoles; Neoplasms; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2022
MEK inhibition suppresses metastatic progression of KRAS-mutated gastric cancer.
    Cancer science, 2022, Volume: 113, Issue:3

    Metastatic progression of tumors is driven by genetic alterations and tumor-stroma interaction. To elucidate the mechanism underlying the oncogene-induced gastric tumor progression, we have developed an organoid-based model of gastric cancer from GAstric Neoplasia (GAN) mice, which express Wnt1 and the enzymes COX2 and microsomal prostaglandin E synthase 1 in the stomach. Both p53 knockout (GAN-p53KO) organoids and KRAS

    Topics: Animals; Disease Models, Animal; Epithelial-Mesenchymal Transition; Mice; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasm Metastasis; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Signal Transduction; Stomach Neoplasms; Tumor Hypoxia; Tumor Microenvironment; Tumor Suppressor Protein p53

2022
Re: Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers.
    European journal of cancer (Oxford, England : 1990), 2022, Volume: 162

    Topics: Fever; Humans; Imidazoles; Neoplasms; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2022
[Administrative delays of temporary recommendation for use: Impact on access to innovation in melanoma].
    Bulletin du cancer, 2022, Volume: 109, Issue:1

    Melanoma has benefited in recent years from therapeutic innovations, which have improved overall survival of patients. France has developed a regulatory arsenal allowing faster access to innovative drugs before marketing authorization: temporary authorization for use (ATU) and temporary recommendation for use (RTU).. We describe here the decision-making processes that led to the non-publication of the decree on the funding of three RTU in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib, and we analyse the fate of these drugs in order to quantify the potential loss of chance.. On 03AUG2018, the French National Agency for Medicines and Health Product Safety (ANSM) published 3 RTU in order to give rapid access to major innovations in adjuvant melanoma therapy: nivolumab, pembrolizumab and the combination of dabrafenib and trametinib. These drugs have respectively demonstrated reductions in the risk of recurrence by 35 %, 43% and 55% for target populations of 2200, 1900 and 650 patients per year. Despite a favourable opinion on reimbursement from the French National Authority for Health (HAS), the decrees on reimbursement will never be published, prohibiting the use of these products before the marketing authorisation, and depriving many patients of a potential cure.. Despite a favourable opinion from scientists and health agencies for the rapid availability of a drug, the French public health code does not systematically imply access to a therapeutic innovation. The reform of access to innovation implemented on 01JUL2021 may help tackle this issue.

    Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Chemotherapy, Adjuvant; Clinical Trials as Topic; Decision Making; Drug Approval; Drug Combinations; France; Humans; Imidazoles; Insurance, Health, Reimbursement; Ipilimumab; Melanoma; Neoplasm Recurrence, Local; Nivolumab; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

2022
Switch from dabrafenib/trametinib combination therapy to encorafenib/binimetinib combination therapy with transition of serum lactate dehydrogenase level in melanoma: A case report.
    Dermatologic therapy, 2022, Volume: 35, Issue:4

    Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Imidazoles; Lactate Dehydrogenases; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides

2022
Lasting Complete Clinical Response of a Recurring Cutaneous Squamous Cell Carcinoma With
    JCO precision oncology, 2022, Volume: 6

    Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Class I Phosphatidylinositol 3-Kinases; Drug Combinations; Humans; Male; MAP Kinase Kinase 1; Metformin; Mutation; Neoplasm Recurrence, Local; Pyridones; Pyrimidinones; Skin Neoplasms; Time Factors; Treatment Outcome

2022
Successful management of an arteriovenous malformation with trametinib in a patient with capillary-malformation arteriovenous malformation syndrome and cardiac compromise.
    Pediatric dermatology, 2022, Volume: 39, Issue:2

    Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is an autosomal dominant condition characterized by multifocal, noncontiguous pink patches on the skin that often have a surrounding pale halo. In some cases, an association with a fast flow, arteriovenous malformation (AVM) can be identified. Here, we describe a case report of a 16-year-old woman with CM-AVM syndrome and significant cardiac compromise successfully treated with trametinib, a mitogen-activated protein kinase (MEK) inhibitor.

    Topics: Adolescent; Arteriovenous Malformations; Capillaries; Female; Humans; p120 GTPase Activating Protein; Port-Wine Stain; Pyridones; Pyrimidinones

2022
Dabrafenib- and trametinib-associated glomerular toxicity: A case report.
    Medicine, 2022, Jan-07, Volume: 101, Issue:1

    Combined treatment with dabrafenib, a B-RAF inhibitor, and trametinib, a mitogen-activated protein kinase inhibitor, is an effective option for patients with metastatic melanoma. A few cases of acute kidney injury associated with tubulointerstitial nephritis and 1 case of nephrotic syndrome have been reported in patients on this drug combination; however, progressive renal injury has not been reported. In this case study, we report a patient with metastatic melanoma who developed glomerular capillary endothelial toxicity and progressive glomerular sclerosis during combination therapy.. Our patient was an 80-year-old woman with a history of type 2 diabetes and chronic kidney disease.. She was diagnosed with metastatic melanoma and commenced combination therapy with dabrafenib and trametinib.. Her renal function progressively deteriorated; by month 20 after treatment commencement, her serum creatinine level had increased from 1.59 to 3.74 mg/dL. The first kidney biopsy revealed marked glomerular and endothelial cell damage. Her medication was stopped, but no improvement was evident. At 5 months after the first biopsy, her serum creatinine level had increased to 5.46 mg/dL; a second kidney biopsy revealed focal segmental glomerular sclerosis and marked tubulointerstitial fibrosis. She was started on hemodialysis.. We describe a patient with a metastatic melanoma who developed progressive kidney failure during treatment with dabrafenib and trametinib. The most prominent microscopy findings were glomerular endothelial damage in the initial kidney biopsy and accelerated glomerular sclerosis and tubulointerstitial fibrosis in the follow-up biopsy. We hypothesize that a decreased renal reserve and impairment of kidney repair capacity caused by inhibition of B-RAF, a downstream mediator of vascular endothelial growth factor, may explain the progressive kidney injury.

    Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Creatinine; Diabetes Mellitus, Type 2; Female; Fibrosis; Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Nephritis, Interstitial; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vascular Endothelial Growth Factor A

2022
Sustained Response to the Mitogen-Activated Extracellular Kinase Inhibitor Trametinib in a Spindle Cell Sarcoma Harboring a QKI-RAF1 Gene Fusion.
    JCO precision oncology, 2022, Volume: 6

    Topics: Adult; Fatal Outcome; Female; Gene Fusion; Humans; Proto-Oncogene Proteins c-raf; Pyridones; Pyrimidinones; RNA-Binding Proteins; Sarcoma; Spinal Cord Neoplasms; Treatment Outcome

2022
DNMT3A facilitates colorectal cancer progression via regulating DAB2IP mediated MEK/ERK activation.
    Biochimica et biophysica acta. Molecular basis of disease, 2022, 04-01, Volume: 1868, Issue:4

    The inactivation of tumor suppressor DOC-2/DAB2 interactive protein (DAB2IP) by epigenetic and post-transcriptional modification has been reported in multiple human malignancies. DNA methyltransferase 3A (DNMT3A) is involved in de novo establishment of DNA methylation and plays a vital role in tumorigenesis. However, whether DNMT3A can regulate colorectal cancer (CRC) progression via modulation of DAB2IP remains unclear. In this study, we revealed that DNMT3A was significantly increased in CRC, predicting a poor overall survival. Functionally, ectopic expression of DNMT3A in CRC cells enhanced cell proliferation, whereas DNMT3A knockdown had the opposite effect by inducing cell cycle arrest. Mechanistically, methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) proved that the expression of DAB2IP was epigenetically suppressed by DNMT3A-mediated promoter methylation in CRC cells. Using dual-luciferase reporter assay and ChIP-PCR assay, we further confirmed that DNMT3A restrained the transcriptional activity of DAB2IP promoter through directly binging to it. In addition, DNMT3A could activate the MEK/ERK signaling pathway via efficiently downregulating DAB2IP. Inhibition of the MEK/ERK cascade abrogated the oncogenic effects of DNMT3A on CRC cells. In conclusion, our study demonstrates that DNMT3A facilitates CRC progression by regulating DAB2IP mediated MEK/ERK activation, providing promising targets for CRC treatment.

    Topics: Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; DNA Methylation; DNA Methyltransferase 3A; Extracellular Signal-Regulated MAP Kinases; Humans; Mitogen-Activated Protein Kinase Kinases; Prognosis; Pyridones; Pyrimidinones; ras GTPase-Activating Proteins; RNA Interference; RNA, Small Interfering; Signal Transduction; Survival Analysis

2022
Pharmacokinetic Interaction Between the MEK1/MEK2 Inhibitor Trametinib and Oral Contraceptives Containing Norethindrone and Ethinyl Estradiol in Female Patients With Solid Tumors.
    Clinical pharmacology in drug development, 2022, Volume: 11, Issue:5

    This phase 1 postapproval study assessed the effect of the mitogen-activated protein kinase kinase enzyme 1/enzyme 2 inhibitor trametinib (2 mg once daily, repeat dosing) on the pharmacokinetics of combined oral contraceptives (COCs) containing norethindrone (NE; 1 mg daily) and ethinyl estradiol (EE; 0.035 mg daily) in 19 female patients with solid tumors. Compared with NE/EE administered without trametinib, NE/EE administered with steady-state trametinib was associated with a clinically nonrelevant 20% increase in NE exposure (area under the curve [AUC]) and no effect on EE exposure (geometric mean ratio [geo-mean] of NE/EE + trametinib to NE/EE [90%CI]: NE AUC calculated to the end of a dosing interval at steady-state [AUC

    Topics: Contraceptives, Oral, Combined; Ethinyl Estradiol; Female; Humans; Male; Neoplasms; Norethindrone; Pyridones; Pyrimidinones

2022
Functional proteomics of patient derived head and neck squamous cell carcinoma cells reveal novel applications of trametinib.
    Cancer biology & therapy, 2022, 12-31, Volume: 23, Issue:1

    In this study, we report a differential response of mitogen-activated protein kinase-kinase (MEK) inhibitor trametinib in 20 head and neck squamous cell carcinoma (HNSCC) patients' tumor-derived cell cultures. Relatively sensitive and resistant cases to trametinib were identified using high throughput metabolic assays and validated in extended dose response studies in vitro. High throughput metabolic assays exploring combination therapies with trametinib were subjected to synergy models and maximal synergistic dose analyses. These yielded several candidates, including axtinib, GDC-0032, GSK-690693, and SGX-523. The combination regimen of trametinib and AXL/MET/VEGFR inhibitor glesatinib showed initial efficacy both in vitro and in vivo (92% reduction in tumor volume). Sensitivity was validated in vivo in a patient-derived xenograft (PDX) model in which trametinib as a single agent effected reduction in tumor volume up to 72%. Reverse Phase Protein Arrays (RPPA) demonstrated differentially expressed proteins and phosphoproteins upon trametinib treatment. Furthermore, resistant cell lines showed a compensatory mechanism via increases in MAPK and non-MAPK pathway proteins that may represent targets for future combination regimens. Intrinsic-targeted options have potential to address paucity of medical treatment options for HNSCC cancer patients, enhance response to extrinsic targeted agents, and/or reduce morbidity as neoadjuvant to surgical treatments.

    Topics: Head and Neck Neoplasms; Humans; Proteomics; Pyridones; Pyrimidinones; Squamous Cell Carcinoma of Head and Neck

2022
Partial response to dabrafenib and trametinib in relapsed BRAF V600E-Mutated multiple myeloma and possible mechanisms of resistance.
    BMJ case reports, 2022, Apr-08, Volume: 15, Issue:4

    BRAF V600E mutations are detected in 3%-10% of patients with multiple myeloma (MM) and are associated with more aggressive disease, higher frequency of extramedullary growth and shorter survival. Monotherapy with the BRAF inhibitor vemurafenib has been disappointing in MM. In patients with BRAF-mutated melanoma, MEK and BRAF inhibition has been a successful approach. Here we describe a very good partial response and possible mechanisms of resistance to a combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in a patient with BRAF V600E-mutant refractory MM.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Mitogen-Activated Protein Kinase Kinases; Multiple Myeloma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2022
Venetoclax-based regimens in combination with trametinib for RAS-mutated relapsed or refractory myeloid malignancies.
    Bone marrow transplantation, 2022, Volume: 57, Issue:6

    Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Neoplasm Recurrence, Local; Pyridones; Pyrimidinones; Sulfonamides

2022
Trametinib for Refractory Chylous Effusions and Systemic Complications in Children with Noonan Syndrome.
    The Journal of pediatrics, 2022, Volume: 248

    To evaluate the effect of the RAS-MAPK pathway inhibitor trametinib on medically refractory chylous effusions in 3 hospitalized patients with Noonan syndrome.. Pharmacologic MEK1/2 inhibition has been used to treat conditions associated with Noonan syndrome, given that activation of RAS-MAPK pathway variants leads to downstream MEK activation. We describe our experience with 3 patients with Noonan syndrome (owing to variants in 3 distinct genes) and refractory chylous effusions treated successfully with MEK inhibition. A monitoring protocol was established to standardize medication dosing and monitoring of outcome measures.. Subjects demonstrated improvement in lymphatic leak with additional findings of improved growth and normalization of cardiac and hematologic measurements. Trametinib was administered safely, with only moderate skin irritation in 1 subject.. Improvements in a variety of quantifiable measurements highlight the potential utility of MEK1/2 inhibition in patients with Noonan syndrome and life-threatening lymphatic disease. Larger, prospective studies are needed to confirm efficacy and assess long-term safety.

    Topics: Antineoplastic Agents; Child; Humans; Mitogen-Activated Protein Kinase Kinases; Noonan Syndrome; Pyridones; Pyrimidinones

2022
Trametinib for a BRAF G469A missense mutation in a neuroblastoma unveiled by liquid biopsy.
    Pediatric blood & cancer, 2022, Volume: 69, Issue:11

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Liquid Biopsy; Mutation; Mutation, Missense; Neuroblastoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2022
Response to trametinib of two pediatric myeloid malignancies cases harboring RAS mutation and monosomy 7.
    Leukemia & lymphoma, 2022, Volume: 63, Issue:9

    Topics: Child; Chromosome Deletion; Chromosomes, Human, Pair 7; Humans; Neoplasms; Pyridones; Pyrimidinones

2022
Safety of combining dabrafenib plus trametinib in elderly BRAF V600 mutation-positive advanced melanoma patients: real-world data analysis of Spanish patients (ELDERLYMEL).
    Melanoma research, 2022, 10-01, Volume: 32, Issue:5

    Efficacy and safety of dabrafenib and trametinib in metastatic melanoma have been demonstrated in two-phase III and one-phase I/II clinical trials. However, patients at least 75 years old (y.o.) were largely underrepresented. Additionally, the safety profile of dabrafenib and trametinib based on age is unknown. ELDERLYMEL is a retrospective noninterventional multicenter study, describing the effectiveness and safety of at least 75 y.o. patients compared with less than 75 y.o. patients with advanced BRAF V600-mutated melanoma treated with dabrafenib plus trametinib or dabrafenib monotherapy. A total of 159 patients were included, 130 less than 75 y.o. and 29 at least 75 y.o. Clinical features were similar between the groups, except in the number of comorbidities, number of metastatic sites, Eastern Cooperative Oncology Group (ECOG) performance status, and BRAF V600-mutation type. Five patients per group received dabrafenib monotherapy. There were no differences in adverse events (AEs) rate or grade between the groups. However, AE profiles were different between the groups, being pyrexia infrequent in patients at least 75 y.o. (13.8% vs. 42.3%; P = 0.005). Dabrafenib and trametinib dose intensities were lower in at least 75 y.o. patients ( P = 0.018 and P = 0.020), but there were no differences in effectiveness between the groups. Finally, in a multivariate analysis, sex (female) was the only variable independently associated with an increased risk of AE grade ≥3. Data from the ELDERLYMEL study demonstrate that dabrafenib plus trametinib is safe and effective in at least 75 y.o. patients with advanced BRAF V600-mutated melanoma without increasing toxicity. Additionally, we describe a different safety profile depending on age and sex.

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Data Analysis; Female; Humans; Imidazoles; Male; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

2022
Regulation of TORC1 by MAPK Signaling Determines Sensitivity and Acquired Resistance to Trametinib in Pediatric BRAFV600E Brain Tumor Models.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2022, 09-01, Volume: 28, Issue:17

    We investigated why three patient-derived xenograft (PDX) childhood BRAFV600E-mutant brain tumor models are highly sensitive to trametinib. Mechanisms of acquired resistance selected in situ, and approaches to prevent resistance were also examined, which may translate to both low-grade glioma (LGG) molecular subtypes.. Sensitivity to trametinib [MEK inhibitor (MEKi)] alone or in combination with rapamycin (TORC1 inhibitor), was evaluated in pediatric PDX models. The effect of combined treatment of trametinib with rapamycin on development of trametinib resistance in vivo was examined. PDX tissue and tumor cells from trametinib-resistant xenografts were characterized.. In pediatric models TORC1 is activated through ERK-mediated inactivation of the tuberous sclerosis complex (TSC): consequently inhibition of MEK also suppressed TORC1 signaling. Trametinib-induced tumor regression correlated with dual inhibition of MAPK/TORC1 signaling, and decoupling TORC1 regulation from BRAF/MAPK control conferred trametinib resistance. In mice, acquired resistance to trametinib developed within three cycles of therapy in all three PDX models. Resistance to trametinib developed in situ is tumor-cell-intrinsic and the mechanism was tumor line specific. Rapamycin retarded or blocked development of resistance.. In these three pediatric BRAF-mutant brain tumors, TORC1 signaling is controlled by the MAPK cascade. Trametinib suppressed both MAPK/TORC1 pathways leading to tumor regression. While low-dose intermittent rapamycin to enhance inhibition of TORC1 only modestly enhanced the antitumor activity of trametinib, it prevented or retarded development of trametinib resistance, suggesting future therapeutic approaches using rapamycin analogs in combination with MEKis that may be therapeutically beneficial in both KIAA1549::BRAF- and BRAFV600E-driven gliomas.

    Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Disease Models, Animal; Glioma; Humans; Mechanistic Target of Rapamycin Complex 1; Mice; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sirolimus

2022
Detection of BRAFV600E by digital PCR on fine-needle aspirate enables rapid initiation of dabrafenib and trametinib in unresectable anaplastic thyroid carcinoma.
    European journal of endocrinology, 2022, Sep-01, Volume: 187, Issue:3

    Recently, targeted therapies using BRAFV600E and MEK inhibitors (dabrafenib and trametinib, respectively) have been recommended in BRAF-mutated anaplastic thyroid carcinoma (ATC). Considering the fast development of ATC, droplet digital PCR (ddPCR) performed on fine-needle aspirate (FNA), which is a rapid, reliable, and low-cost method, appears interesting for the detection of BRAFV600E mutation in these patients and allows early initiation of targeted therapies.. In our two patients, both presenting extensive cervical masses inaccessible to surgery, ddPCR results were available in less than 24 h. Therefore, dabrafenib and trametinib were started only a few days after first contact.. We suggest that ddPCR on FNA be used in non-resectable cervical masses for rapid BRAFV600E mutation detection in the hope that starting targeted therapies early might improve outcomes.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Mutation; Oximes; Polymerase Chain Reaction; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

2022
Response to trametinib in a nonsmall cell lung cancer patient with osimertinib resistance harboring GNAS R201C and R201H mutations: a case report.
    Anti-cancer drugs, 2022, 10-01, Volume: 33, Issue:9

    Osimertinib, an orally administered third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is widely approved for the first-line and second-line treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations. However, the rapid development of osimertinib resistance renders the unsustainable treatment benefit. Patients with EGFR -mutated NSCLC who develop osimertinib resistance, especially those acquiring relatively rare and 'off-target' resistance mutations, still lack effective therapeutic options for postosimertinib therapy. Herein, we reported a 73-year-old woman diagnosed with T1N3M1 lung adenocarcinoma harboring EGFR L858R mutation, who acquired two GNAS mutations (R201C and R201H) and lost the EGFR L858R mutation after progression on icotinib and osimertinib. The patient was subsequently treated with trametinib and there was no obvious tumor increase. Our study revealed that GNAS R201 can confer the osimertinib resistance in EGFR -positive NSCLC, and present the first report of the prevalence of GNAS R201C and R201H mutants in NSCLC which response to trametinib treatment. Our case suggests that trametinib could be a treatment option in NSCLC patients harboring GNAS -activating mutations.

    Topics: Acrylamides; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Chromogranins; ErbB Receptors; Female; GTP-Binding Protein alpha Subunits, Gs; Humans; Indoles; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Pyrimidinones

2022
A distinct four-value blood signature of pyrexia under combination therapy of malignant melanoma with dabrafenib and trametinib evidenced by an algorithm-defined pyrexia score.
    PloS one, 2022, Volume: 17, Issue:8

    Pyrexia is a frequent adverse event of BRAF/MEK-inhibitor combination therapy in patients with metastasized malignant melanoma (MM). The study's objective was to identify laboratory changes which might correlate with the appearance of pyrexia. Initially, data of 38 MM patients treated with dabrafenib plus trametinib, of which 14 patients developed pyrexia, were analysed retrospectively. Graphical visualization of time series of laboratory values suggested that a rise in C-reactive-protein, in parallel with a fall of leukocytes and thrombocytes, were indicative of pyrexia. Additionally, statistical analysis showed a significant correlation between lactate dehydrogenase (LDH) and pyrexia. An algorithm based on these observations was designed using a deductive and heuristic approach in order to calculate a pyrexia score (PS) for each laboratory assessment in treated patients. A second independent data set of 28 MM patients, 8 with pyrexia, was used for the validation of the algorithm. PS based on the four parameters CRP, LDH, leukocyte and thrombocyte numbers, were statistically significantly higher in pyrexia patients, differentiated between groups (F = 20.8; p = <0.0001) and showed a significant predictive value for the diagnosis of pyrexia (F = 6.24; p = 0.013). We provide first evidence that pyrexia in patients treated with BRAF/MEK-blockade can be identified by an algorithm that calculates a score.

    Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Fever; Humans; Imidazoles; L-Lactate Dehydrogenase; Melanoma; Melanoma, Cutaneous Malignant; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

2022
First-line pembrolizumab versus dabrafenib/trametinib treatment for BRAF V600-mutant advanced melanoma.
    Journal of the American Academy of Dermatology, 2022, Volume: 87, Issue:5

    Limited data are available to assist the selection between immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors as first-line treatment for patients with BRAF-mutant advanced malignant melanoma.. To investigate the outcomes associated with first-line pembrolizumab or dabrafenib/trametinib treatment for advanced melanoma with activating BRAF V600 mutation.. Data of patients with BRAF V600-mutant melanoma who were treated with first-line pembrolizumab (n = 40) or dabrafenib/trametinib (n = 32) were analyzed. Tumor response, progression-free survival, and overall survival were evaluated. Immune evasion accompanied with emerging resistance to BRAF/mitogen-activated protein kinase kinase inhibitors was assessed.. A longer overall survival was observed after first-line pembrolizumab treatment than after first-line dabrafenib/trametinib treatment (hazard ratio = 2.910, 95% CI: 1.552-5.459), although there were no significant differences in progression-free survival (P = .375) and response rate (P = .123). Emergence of resistance to dabrafenib/trametinib co-occurred with immune evasion, enabling melanoma cells to escape recognition and killing by Melan-A-specific CD8. Analysis was conducted in a retrospective manner.. Pembrolizumab may be recommended over BRAF/mitogen-activated protein kinase kinase inhibitors as the first-line treatment in patients with advanced BRAF V600-mutant melanoma.

    Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; CD8-Positive T-Lymphocytes; Humans; Imidazoles; Immune Checkpoint Inhibitors; MART-1 Antigen; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

2022
Response to osimertinib plus trametinib in a heavily treated epidermal growth factor receptor (EGFR)-positive NSCLC harboring a rare, acquired rapidly accelerated fibrosarcoma B-type (BRAF) p.D594N mutation: a case report.
    Anti-cancer drugs, 2022, 10-01, Volume: 33, Issue:9

    Heterogeneity in the acquired genetic cause of osimertinib resistance leads to difficulties in understanding and addressing molecular mechanisms of resistance in clinical practice. Recent studies and clinical cases established that altered BRAF could drive osimertinib resistance in an EGFR-independent manner. Herein, we present a case in which an EGFR-positive, MET-amplified nonsmall cell lung cancer (NSCLC) patient acquired BRAF p.D594N mutation on third-line osimertinib plus crizotinib and responded to seventh-line treatment with osimertinib plus MEK inhibitor trametinib. Disease control was maintained for 6 months. BRAF p.D594N is a kinase impaired mutation but leads to increased MEK/ERK signaling, which could activate the downstream signaling of EGFR and induce drug resistance. There has been preclinical evidence supporting dual inhibition of MEK and EGFR for overcoming this resistance. To the best of our knowledge, our case is the first to provide clinical evidence that trametinib plus osimertinib was effective for EGFR-mutant NSCLC patients with acquired BRAF p.D594N mutation. More supporting data and systematic validation studies are needed for comprehensive understanding of this therapy strategy and future applications.

    Topics: Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; ErbB Receptors; Fibrosarcoma; Humans; Indoles; Lung Neoplasms; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones

2022
Severe Lymphatic Disorder and Multifocal Atrial Tachycardia Treated with Trametinib in a Patient with Noonan Syndrome and SOS1 Mutation.
    Genes, 2022, 08-23, Volume: 13, Issue:9

    Noonan syndrome (NS) is a multisystemic disorder caused by germline mutations in the Ras/MAPK cascade, causing a broad spectrum of phenotypical abnormalities, including abnormal facies, developmental delay, bleeding diathesis, congenital heart disease (mainly pulmonary stenosis and hypertrophic cardiomyopathy), lymphatic disorders, and uro-genital abnormalities. Multifocal atrial tachycardia has been associated with NS, where it may occur independently of hypertrophic cardiomyopathy. Trametinib, a highly selective MEK1/2 inhibitor currently approved for the treatment of cancer, has been shown to reverse left ventricular hypertrophy in two RIT1-mutated newborns with NS and severe hypertrophic cardiomyopathy. Severe lymphatic abnormalities may contribute to decreased pulmonary compliance in NS, and pulmonary lymphangiectasias should be included in the differential diagnosis of a newborn requiring prolonged oxygen administration. Herein we report the case of a pre-term newborn who was admitted to our unit for the occurrence of severe respiratory distress and subentrant MAT treated with trametinib.

    Topics: Cardiomyopathy, Hypertrophic; Humans; Infant, Newborn; Mutation; Noonan Syndrome; Oxygen; Pyridones; Pyrimidinones; ras Proteins; Tachycardia

2022
MITOGEN-ACTIVATED PROTEIN INHIBITORS: FULL-FIELD ELECTRORETINOGRAM DEMONSTRATING GENERALIZED RETINAL DYSFUNCTION.
    Retinal cases & brief reports, 2022, Mar-01, Volume: 16, Issue:2

    To report a patient with generalized retinal toxicity to mitogen-activated protein inhibitors.. Retrospective case report.. Full-field electroretinogram findings indicate a generalized toxicity to the use of the mitogen-activated protein inhibitor trametinib. There was an improved response and resolution of serous detachments after decreasing the dose.. Mitogen-activated protein inhibitors may affect global retinal function, as opposed to the serous detachments that are concentrated in the posterior pole. This may be of importance in further understanding the underlying pathologic mechanisms.

    Topics: Electroretinography; Humans; Pyridones; Pyrimidinones; Retina; Retrospective Studies

2022
A case of Vogt-Koyanagi-Harada-like uveitis secondary to dabrafenib/trametinib therapy for advanced melanoma.
    European journal of ophthalmology, 2022, Volume: 32, Issue:1

    We report a case of ocular drug toxicity consistent with bilateral Vogt-Koyanagi-Harada (VKH) like disease in a patient with cutaneous melanoma treated with Dabrafenib/Trametinib therapy. A 53-year-old man with a history of metastatic cutaneous melanoma, treated with Dabrafenib/Trametinib, developed a severe acute panuveitis with granulomatous anterior uveitis and multiple serous retinal detachments. The ocular inflammatory reaction was classified as a bilateral Vogt-Koyanagi-Harada disease. Intraocular inflammation resolved after discontinuation of chemotherapeutic agents and aggressive topical and systemic corticosteroid therapy. The present case outlines the importance of recognizing VKH-like syndrome as a possible consequence of therapy with dabrafenib and trametinib.

    Topics: Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Uveitis; Uveomeningoencephalitic Syndrome

2022
Clinical features of acute kidney injury in patients receiving dabrafenib and trametinib.
    Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2022, 02-25, Volume: 37, Issue:3

    Our objective was to characterize the incidence, risk factors and clinical features of acute kidney injury (AKI) in patients receiving dabrafenib and trametinib.. We performed a retrospective cohort study examining the kidney outcomes of patients in a large healthcare system who received dabrafenib/trametinib between 2010 and 2019. The primary outcome was AKI, defined as a 1.5-fold increase in serum creatinine from baseline within a 12-month study period. AKI severity and etiology was determined for each case by chart review. Logistic regression was used to evaluate baseline predictors of AKI.. A total of 199 patients who received dabrafenib in our healthcare system from 2010 to 2019 were included in the analysis. Forty-two patients (21%) experienced AKI within 12 months; 10 patients (5% of the total cohort, 24% of AKI patients) experienced AKI occurring during a dabrafenib/trametinib-induced febrile syndrome characterized by fever, chills, gastrointestinal symptoms and elevated liver enzymes. Preexisting liver disease was the only significant predictor of AKI in the cohort. One patient had biopsy-proven granulomatous acute interstitial nephritis that resolved with corticosteroids.. Oncologists and nephrologists should be aware that AKI is common after dabrafenib/trametinib and a substantial number of cases occur in the setting of treatment-induced pyrexia.

    Topics: Acute Kidney Injury; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies

2022
Bilateral facial neuritis associated with dabrafenib and trametinib after failure of neoadjuvant immunotherapy for stage III melanoma.
    ANZ journal of surgery, 2022, Volume: 92, Issue:1-2

    Topics: Antineoplastic Combined Chemotherapy Protocols; Facial Nerve Diseases; Humans; Imidazoles; Immunotherapy; Melanoma; Mutation; Neoadjuvant Therapy; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2022
Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600
    Annales de dermatologie et de venereologie, 2022, Volume: 149, Issue:1

    We analysed PCD/T in patients treated with D+T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results.. We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0ng/mL; interquartile range (IQR) [4-945]) and of PCT (median: 8.6ng/mL; IQR [5-39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P=0.06). However, no difference was observed between mean PCD/T of progressing patients (n=21; 125±183ng/mL and 9.3±3.6ng/mL, respectively) and responders (complete, partial or stable response) (n=13; 159±225ng/mL, P=0.58 and 10.6±24.4ng/mL, P=0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n=16) was significantly higher for female subjects (n=18; 11.5±4.8ng/mL) than for male subjects (8.8ng/mL±2.9, P=0.01), but no difference was observed between sex and CPD (P=0.32).. Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2022
Kirsten rat sarcoma viral oncogene homolog G12C mutant advanced non-small-cell lung cancer treated with MEK1/2 inhibitor trametinib: a case report.
    Anti-cancer drugs, 2022, 01-01, Volume: 33, Issue:1

    No targeted therapies are approved for non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation to date. Trametinib, a selective allosteric inhibitor of the MEK1/2, demonstrated debatable clinical activity in KRAS-mutant NSCLC. In this case, we present a recurrent advanced NSCLC with KRAS G12C mutation successfully treated with single-agent trametinib therapy. An 87-year-old man who underwent radiotherapy for the right lung adenocarcinoma was admitted to clinical oncology center for recurrent lesions in bilateral lungs. He was unwilling to perform second-line chemotherapy, but underwent molecular profiling and revealed the KRAS G12C mutation. The single-agent target therapy of trametinib showed clinical benefit without obvious toxicity. Furthermore, this report reviewed the previous date of the preclinical and clinical and summarized that KRAS G12C mutation may be more sensitive to the inhibition of mitogen-activated protein kinase kinase. This case advocates for routine screening of KRAS point mutations in the utility of precision medicine and suggests that treatment with trametinib in advanced NSCLC cases with KRAS G12C mutation is well tolerated and effective, especially for those very elderly or unsuitable for more aggressive chemotherapy.

    Topics: Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Mitogen-Activated Protein Kinase Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones

2022
Molecular Management of Multifocal Atrial Tachycardia in Noonan's Syndrome With MEK1/2 Inhibitor Trametinib.
    Circulation. Genomic and precision medicine, 2021, Volume: 14, Issue:5

    Topics: Female; Humans; Infant, Newborn; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Noonan Syndrome; Point Mutation; Proto-Oncogene Proteins c-raf; Pyridones; Pyrimidinones; Tachycardia

2021
Targeting enhancer reprogramming to mitigate MEK inhibitor resistance in preclinical models of advanced ovarian cancer.
    The Journal of clinical investigation, 2021, 10-15, Volume: 131, Issue:20

    Ovarian cancer is characterized by aberrant activation of the mitogen-activated protein kinase (MAPK), highlighting the importance of targeting the MAPK pathway as an attractive therapeutic strategy. However, the clinical efficacy of MEK inhibitors is limited by intrinsic or acquired drug resistance. Here, we established patient-derived ovarian cancer models resistant to MEK inhibitors and demonstrated that resistance to the clinically approved MEK inhibitor trametinib was associated with enhancer reprogramming. We also showed that enhancer decommissioning induced the downregulation of negative regulators of the MAPK pathway, leading to constitutive ERK activation and acquired resistance to trametinib. Epigenetic compound screening uncovered that HDAC inhibitors could alter the enhancer reprogramming and upregulate the expression of MAPK negative regulators, resulting in sustained MAPK inhibition and reversal of trametinib resistance. Consequently, a combination of HDAC inhibitor and trametinib demonstrated a synergistic antitumor effect in vitro and in vivo, including patient-derived xenograft mouse models. These findings demonstrated that enhancer reprogramming of the MAPK regulatory pathway might serve as a potential mechanism underlying MAPK inhibitor resistance and concurrent targeting of epigenetic pathways and MAPK signaling might provide an effective treatment strategy for advanced ovarian cancer.

    Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Drug Resistance, Neoplasm; Enhancer Elements, Genetic; Female; Histone Deacetylase Inhibitors; Humans; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Ovarian Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2021
HRAS is a therapeutic target in malignant chemo-resistant adenomyoepithelioma of the breast.
    Journal of hematology & oncology, 2021, 09-08, Volume: 14, Issue:1

    Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. Chemotherapy has been used in the management of advanced AME patients, however the majority of treatments are not effective. Recent studies report recurrent mutations in the HRAS Q61 hotspot in small series of AMEs, but there are no preclinical or clinical data showing H-Ras protein as a potential therapeutic target in malignant AMEs. We performed targeted sequencing of tumours' samples from new series of 13 AMEs, including 9 benign and 4 malignant forms. Samples from the breast tumour and the matched axillary metastasis of one malignant HRAS mutated AME were engrafted and two patient-derived xenografts (PDX) were established that reproduced the typical AME morphology. The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). All malignant AMEs presented a recurrent mutation in the HRAS G13R or G12S hotspot. Mutation of PIK3CA were found in both benign and malignant AMEs, while AKT1 mutations were restricted to benign AMEs. Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors.

    Topics: Adenomyoepithelioma; Aged; Aged, 80 and over; Antineoplastic Agents; Breast; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Imidazoles; Middle Aged; Oximes; Point Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones

2021
BRAF V600E Mediates Crizotinib Resistance and Responds to Dabrafenib and Trametinib in a ROS1-Rearranged Non-Small Cell Lung Cancer: A Case Report.
    The oncologist, 2021, Volume: 26, Issue:12

    Crizotinib, a multitargeted MET/ALK/ROS1 tyrosine kinase inhibitor, has been approved for the treatment of ROS1 fusion-positive non-small cell lung cancers (NSCLCs). However, "on-target" or "off-target" resistance alterations often emerge that confer the drug resistance. Patients with ROS1-rearranged NSCLC who develop crizotinib resistance, especially those acquiring "off-target" resistance mutations, still lack effective therapeutic options for after crizotinib treatment. Herein, we reported a patient with stage IVb lung adenocarcinoma harboring ROS1 fusion, who acquired a BRAF V600E and lost the ROS1 fusion after progression on crizotinib. It was deduced that the V600E may originate from a subclone with an extremely low fraction that was independent of ROS1 fusion-positive cells. The patient was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months. Our study revealed that BRAF V600E can confer the crizotinib resistance in ROS1 fusion-positive NSCLC and presented the first case showing that the treatment with dabrafenib and trametinib can serve as an effective option for later-line treatment for this molecular-defined subgroup. KEY POINTS: Patients with ROS1-rearranged non-small cell lung cancer (NSCLC) who acquire "off-target" resistance mutations to crizotinib still lack effective therapeutic options for after crizotinib treatment. This report describes the case of a patient with ROS1-rearranged NSCLC who acquired a BRAF V600E and lost the ROS1 fusion after crizotinib failure. The case was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months. This is the first article reporting that treatment with dabrafenib and trametinib may serve as an effective option for later-line treatment for patients harboring resistant BRAF V600E.

    Topics: Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Humans; Imidazoles; Lung Neoplasms; Oximes; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
Retrospective analysis of adjuvant therapy using dabrafenib plus trametinib in Japanese patients with advanced melanoma: analysis of 36 cases.
    Melanoma research, 2021, 12-01, Volume: 31, Issue:6

    Patients with resected stage IIIB, IIIC and IIID melanomas have a high risk of recurrence. Therefore, an appropriate protocol for stage III melanoma is needed. Since adjuvant dabrafenib plus trametinib (D+T) combined therapy and anti-PD1 antibody (Ab) therapy reduce the risk of recurrence in patients with resected stage III BRAF-mutated melanoma, selecting the adjuvant therapy for BRAF-mutated melanoma is controversial. The efficacy and safety profiles of D+T combined therapy in the adjuvant setting were retrospectively analyzed in 36 Japanese. BRAF-mutated advanced melanoma patients. The relapse-free rate (RFR) at 12 months was 82.1% (95% confidential interval (CI), 63.9-92.6%). In the 21 patients who completed the protocol, the RFR at 12 months was 85.7% (95% CI, 64.5-95.9%). In the seven patients whose protocol was interrupted by adverse events, the RFR was 71.4% (95% CI, 35.2-92.4%). The incidence rate of any AEs for all patients was 69.7% (95% CI, 52.5-82.8%), including 13 cases of pyrexia, five cases of skin rash and four cases of liver dysfunction. The present study suggested that D+T therapy in the adjuvant setting is a useful and very tolerable protocol for BRAF-mutated melanoma in the Japanese population.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Female; Humans; Imidazoles; Japan; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Survival Analysis

2021
Enhancing Therapeutic Efficacy of Oncolytic Herpes Simplex Virus with MEK Inhibitor Trametinib in Some BRAF or KRAS-Mutated Colorectal or Lung Carcinoma Models.
    Viruses, 2021, 09-03, Volume: 13, Issue:9

    Oncolytic virus (OV) as a promising therapeutic agent can selectively infect and kill tumor cells with naturally inherited or engineered properties. Considering the limitations of OVs monotherapy, combination therapy has been widely explored. MEK inhibitor (MEKi) Trametinib is an FDA-approved kinase inhibitor indicated for the treatment of tumors with BRAF V600E or V600K mutations. In this study, the oncolytic activity in vitro and anti-tumor therapeutic efficacy in vivo when combined with oHSV and MEKi Trametinib were investigated. We found: (1) Treatment with MEKi Trametinib augmented oHSV oncolytic activity in BRAF V600E-mutated tumor cells. (2) Combination treatment with oHSV and MEKi Trametinib enhanced virus replication mediated by down-regulation of STAT1 and PKR expression or phosphorylation in BRAF V600E-mutated tumor cells as well as BRAF wt/KRAS-mutated tumor cells. (3) A remarkably synergistic therapeutic efficacy was shown in vivo for BRAF wt/KRAS-mutated tumor models, when a combination of oHSV including PD-1 blockade and MEK inhibition. Collectively, these data provide some new insights for clinical development of combination therapy with oncolytic virus, MEK inhibition, and checkpoint blockade for BRAF or KRAS-mutated tumors.

    Topics: Animals; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Chlorocebus aethiops; Colorectal Neoplasms; Female; Humans; Lung; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Oncolytic Virotherapy; Oncolytic Viruses; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Simplexvirus; STAT1 Transcription Factor; Vero Cells

2021
Management of Pyrexia Associated with the Combination of Dabrafenib and Trametinib: Canadian Consensus Statements.
    Current oncology (Toronto, Ont.), 2021, 09-14, Volume: 28, Issue:5

    The combination of dabrafenib and trametinib is a well-established treatment for BRAF-mutated melanoma. However, the effectiveness of this approach may be hindered by the development of treatment-related pyrexia syndrome, which occurs in at least 50% of treated patients. Without appropriate intervention, pyrexia syndrome has the potential to worsen and can result in hypotension secondary to dehydration and associated organ-related complications. Furthermore, premature treatment discontinuation may result in a reduction in progression-free and overall survival. Despite existing guidance, there is still a wide variety of therapeutic approaches suggested in the literature for both the definition and management of dabrafenib and trametinib-related pyrexia. This is reflected in the practice variation of its prevention and treatment within and between Canadian cancer centres. A Canadian working group was formed and consensus statements were constructed based on evidence and finalised through a two-round modified Delphi approach. The statements led to the development of a pyrexia treatment algorithm that can easily be applied in routine practice. The Canadian working group consensus statements serve to provide practical guidance for the management of dabrafenib and trametinib-related pyrexia, hopefully leading to reduced discontinuation rates, and ultimately improve patients' quality of life and cancer-related outcomes.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Canada; Consensus; Fever; Humans; Imidazoles; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quality of Life

2021
Stereotactic body radiotherapy plus pembrolizumab and trametinib for pancreatic cancer.
    The Lancet. Oncology, 2021, Volume: 22, Issue:10

    Topics: Antibodies, Monoclonal, Humanized; Humans; Pancreatic Neoplasms; Pyridones; Pyrimidinones; Radiosurgery

2021
Stereotactic body radiotherapy plus pembrolizumab and trametinib for pancreatic cancer - Authors' reply.
    The Lancet. Oncology, 2021, Volume: 22, Issue:10

    Topics: Antibodies, Monoclonal, Humanized; Humans; Pancreatic Neoplasms; Pyridones; Pyrimidinones; Radiosurgery

2021
Connective tissue panniculitis and vitiligo in a patient with stage IV melanoma achieving complete response to dabrafenib and trametinib combination therapy.
    Melanoma research, 2021, 12-01, Volume: 31, Issue:6

    The combination of BRAF and MEK inhibitors, such as dabrafenib and trametinib, respectively, is an established treatment option for patients with advanced BRAFV600-mutated melanoma. With the wide adoption of these therapies, a range of cutaneous adverse effects has been reported. We describe the case of a 47-year-old woman with BRAFV600E-mutated stage IV melanoma treated with dabrafenib and trametinib for 30 months who presented to our attention for painful skin lesions that had been present on her limbs since the start of targeted therapy. We also observed vitiligo-like lesions on the extensor surface of both legs. Despite achieving a complete oncological response, the patient had to discontinue the treatment because of persisting fever, nausea and painful skin nodules that significantly impaired her quality of life. The recognition of cutaneous signs of efficacy of such drugs for advanced melanoma is of primary importance in order to identify patients with potential long-term clinical benefits.

    Topics: Combined Modality Therapy; Female; Humans; Imidazoles; Melanoma; Middle Aged; Neoplasm Staging; Oximes; Panniculitis; Pyridones; Pyrimidinones; Skin Neoplasms; Vitiligo

2021
Quantifying ERK activity in response to inhibition of the BRAFV600E-MEK-ERK cascade using mathematical modelling.
    British journal of cancer, 2021, Volume: 125, Issue:11

    Simultaneous inhibition of multiple components of the BRAF-MEK-ERK cascade (vertical inhibition) has become a standard of care for treating BRAF-mutant melanoma. However, the molecular mechanism of how vertical inhibition synergistically suppresses intracellular ERK activity, and consequently cell proliferation, are yet to be fully elucidated.. We develop a mechanistic mathematical model that describes how the mutant BRAF inhibitor, dabrafenib, and the MEK inhibitor, trametinib, affect BRAFV600E-MEK-ERK signalling. The model is based on a system of chemical reactions that describes cascade signalling dynamics. Using mass action kinetics, the chemical reactions are re-expressed as ordinary differential equations that are parameterised by in vitro data and solved numerically to obtain the temporal evolution of cascade component concentrations.. The model provides a quantitative method to compute how dabrafenib and trametinib can be used in combination to synergistically inhibit ERK activity in BRAFV600E-mutant melanoma cells. The model elucidates molecular mechanisms of vertical inhibition of the BRAFV600E-MEK-ERK cascade and delineates how elevated BRAF concentrations generate drug resistance to dabrafenib and trametinib. The computational simulations further suggest that elevated ATP levels could be a factor in drug resistance to dabrafenib.. The model can be used to systematically motivate which dabrafenib-trametinib dose combinations, for treating BRAFV600E-mutated melanoma, warrant experimental investigation.

    Topics: Extracellular Signal-Regulated MAP Kinases; Humans; Imidazoles; MAP Kinase Signaling System; Melanoma; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Models, Chemical; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
Cost-Effectiveness of the Dabrafenib Schedule in Combination With Trametinib Compared With Other Targeted Therapies, Immunotherapy, and Dacarbazine for the Treatment of Unresectable or Metastatic Melanoma With BRAFV600 Mutation in Colombia.
    Value in health regional issues, 2021, Volume: 26

    Advanced melanoma accounts for 4% of malignant skin tumors, and approximately 80% of deaths are attributed to it. The most frequent mutation of the RAF gene is BRAFV600, which has been associated with a worse prognosis. The objective of the research was to evaluate the cost-effectiveness of the combined regimen of dabrafenib plus trametinib (D + T) compared with other targeted therapies, immunotherapy, and dacarbazine for the treatment of unresectable/metastatic melanoma with BRAFV600 mutation from the perspective of the Colombian health system.. A partitioned survival model with 3 states (progression-free survival, progression, and death) was used to evaluate the cost-effectiveness for a time horizon of 20 years. Owing to the perspective of the analysis, only direct medical costs were taken into account. The efficacy of the evaluated treatment and the comparators were measured in terms of overall survival and progression-free survival. All costs were expressed in Colombian pesos as of 2018, and outcomes and costs were discounted at 5% annually. Two analysis scenarios were considered, one in which only monitoring and follow-up costs were included in the progression phase and another in which costs of acquisition of possible treatment sequences were also included.. In the first scenario (without postprogression medication costs), the combined D + T regimen was a dominant alternative to vemurafenib + cobimetinib but was not a cost-effective option compared with vemurafenib, nivolumab, ipilimumab, nivolumab + ipilimumab, pembrolizumab, and dacarbazine. In the second scenario (with drug costs in postprogression), D + T was dominant compared with vemurafenib + cobimetinib and cost-effective compared with nivolumab and pembrolizumab. Compared with other schemes, the incremental cost-effectiveness ratio was above the threshold of 3 gross domestic product per capita. Probabilistic sensitivity analyses showed that a willingness-to-pay threshold of Col$56 484 300 (US$19 108) per quality-adjusted life-year would not be reached at the current price of schema in Colombia.. The combined scheme could be a cost-effective and even a cost-saving alternative to vemurafenib + cobimetinib, nivolumab, and pembrolizumab if the costs associated with the use of other medications are taken into account after progression to the first line of treatment. Compared with the other comparators, it produces a greater number of quality-adjusted life-years, but the incremental cost-effectiveness ratio is above that of the willingness to pay.

    Topics: Colombia; Cost-Benefit Analysis; Dacarbazine; Humans; Imidazoles; Immunotherapy; Melanoma; Mutation; Oximes; Pyridones; Pyrimidinones

2021
Pharmacologic control of homeostatic and antigen-driven proliferation to target HIV-1 persistence.
    Biochemical pharmacology, 2021, Volume: 194

    The presence of latent human immunodeficiency virus 1 (HIV-1) in quiescent memory CD4 + T cells represents a major barrier to viral eradication. Proliferation of memory CD4 + T cells is the primary mechanism that leads to persistence of the latent reservoir, despite effective antiretroviral therapy (ART). Memory CD4 + T cells are long-lived and can proliferate through two mechanisms: homeostatic proliferation via γc-cytokine stimulation or antigen-driven proliferation. Therefore, therapeutic modalities that perturb homeostatic and antigen-driven proliferation, combined with ART, represent promising strategies to reduce the latent reservoir. In this study, we investigated a library of FDA-approved oncology drugs to determine their ability to inhibit homeostatic and/or antigen-driven proliferation. We confirmed potential hits by evaluating their effects on proliferation in memory CD4 + T cells from people living with HIV-1 on ART (PLWH) and interrogated downstream signaling of γc-cytokine stimulation. We found that dasatinib and ponatinib, tyrosine kinase inhibitors, and trametinib, a MEK inhibitor, reduced both homeostatic and antigen-driven proliferationby >65%, with a reduction in viability <45%, ex vivo. In memory CD4 + T cells from PLWH, only dasatinib restricted both homeostatic and antigen-driven proliferation and prevented spontaneous rebound, consistent with promoting a smaller reservoir size. We show that dasatinib restricts IL-7 induced proliferation through STAT5 phosphorylation inhibition. Our results establish that the anti-cancer agent dasatinib is an exciting candidate to be used as an anti-proliferative drug in a clinical trial, since it efficiently blocks proliferation and iswell tolerated in patients with chronic myeloid leukemia (CML).

    Topics: Antigens, Viral; Cell Proliferation; Cells, Cultured; Dasatinib; Drug Delivery Systems; HIV Infections; HIV-1; Homeostasis; Humans; Imidazoles; Leukocytes, Mononuclear; Protein Kinase Inhibitors; Pyridazines; Pyridones; Pyrimidinones

2021
Cautious addition of targeted therapy to PD-1 inhibitors after initial progression of BRAF mutant metastatic melanoma on checkpoint inhibitor therapy.
    BMC cancer, 2021, Nov-07, Volume: 21, Issue:1

    Virtually all metastatic patients with metastatic melanoma who progress after initial treatment with PD-1 or CTLA-4 directed antibodies will die of their disease. Salvage options are urgently needed. It is theoretically attractive to combine immunotherapy with targeted agents in progressing patients with BRAF mutation positive melanoma, but the toxicity of combined treatment has proven challenging.. We performed a retrospective analysis of our patient database and identified 23 patients who progressed on initial checkpoint inhibitor treatment, who subsequently had cautious addition of BRAF±MEK inhibitor therapy to continued PD-1 antibody treatment.. We found an objective response rate of 55% in second line therapy, with a median progression-free survival of 33.4 months and median overall survival of 34.1 months, with 40% of patients in unmaintained remission at over 3 years. Ten of 12 responding patients were able to discontinue all therapy and continue in unmaintained remission. Toxicity of this approach was generally manageable (21.7% grade 3-5 toxicity). There was 1 early sudden death for unknown reasons in a responding patient.. Our results suggest that 2nd line therapy with PD-1 inhibitors plus BRAF±MEK inhibitors has substantial activity and manageable toxicity. This treatment can induce additional durable complete responses in patients who have progressed on initial immunotherapy. These results suggest further evaluation be performed of sequential PD-1 antibody treatment with cautious addition of targeted therapy in appropriate patients.

    Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Combined Modality Therapy; Disease Progression; Feasibility Studies; Female; Humans; Imidazoles; Immune Checkpoint Inhibitors; Ipilimumab; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Mutation; Nivolumab; Oximes; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Time Factors; Treatment Outcome; Young Adult

2021
Retrospective Chart Review of Dabrafenib Plus Trametinib in Patients with Metastatic BRAF V600-Mutant Melanoma Treated in the Individual Patient Program (DESCRIBE Italy).
    Targeted oncology, 2021, Volume: 16, Issue:6

    Real-world data on extended follow-up of patients with BRAF V600-mutant metastatic melanoma are limited. We investigated dabrafenib plus trametinib (dab + tram) outside of a clinical trial setting (Individual Patient Program; DESCRIBE Italy).. To describe the baseline features, treatment patterns, efficacy, and safety outcomes in patients with BRAF V600-mutant unresectable or metastatic melanoma who had received dab + tram as part of the Managed Access Program (MAP) in Italy.. An observational, retrospective chart review was conducted in Italian patients with BRAF V600-mutant unresectable stage III/IV melanoma receiving dab + tram as part of the MAP. Baseline features, treatment patterns, efficacy, and safety outcomes were evaluated.. Overall, 499 patients were included in this analysis. BRAF V600E mutation was seen in 81.4% of patients. Overall response rate achieved in 243 of the 390 evaluable patients was 62.3% (95% CI 57.5-67.1). Median progression-free survival (PFS) was 9.3 months (95% CI 8.6-10.6). Subgroup analyses revealed that patients with normal lactate dehydrogenase (LDH) and ≤ three metastatic sites without brain metastases at baseline had better outcomes. With normal LDH at baseline, median PFS for patients with one or two metastatic sites other than cerebral was 18 months. No new safety signals were observed. Treatment was permanently discontinued because of treatment-emergent adverse events (TEAEs) in 9.2% of patients, and pyrexia (27.3%) was the most common TEAE, with a lower incidence than that in the phase 3 studies of dab + tram.. Treatment of BRAF V600E-mutant metastatic melanoma with dab + tram in the real-world setting was effective and safe, including the unselected population with several patients having a high tumor burden - concordant with the results of the pivotal phase 3 studies of dab + tram.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Melanoma, Cutaneous Malignant; Mutation; Neoplasms, Second Primary; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms

2021
Novel Finding of Copy Number Gains in GNAS and Loss of 10q in a Child With Malignant Transformation of Neurocutaneous Melanosis Syndrome.
    JCO precision oncology, 2021, Volume: 5

    Topics: Cell Transformation, Neoplastic; Child; Chromogranins; Chromosome Deletion; Chromosomes, Human, Pair 10; Dexamethasone; DNA Copy Number Variations; GTP-Binding Protein alpha Subunits, Gs; Humans; Laminectomy; Magnetic Resonance Imaging; Male; Melanosis; Neurocutaneous Syndromes; Pyridones; Pyrimidinones

2021
Bilateral Drug-Induced Uveitis and Epiretinal Membrane during the Treatment of a Metastatic Cutaneous Melanoma.
    Ocular immunology and inflammation, 2021, Apr-03, Volume: 29, Issue:3

    Topics: Aged; Antineoplastic Agents; Drug-Related Side Effects and Adverse Reactions; Epiretinal Membrane; Female; Glucocorticoids; Humans; Imidazoles; Liver Neoplasms; Lymphatic Metastasis; Melanoma; Neoplasm Staging; Oximes; Prednisolone; Pyridones; Pyrimidinones; Skin Neoplasms; Tomography, Optical Coherence; Uveitis

2021
Trametinib-associated Hyponatremia in a Child With Low-grade Glioma is Not Seen Following Treatment With Alternative MEK Inhibitor.
    Journal of pediatric hematology/oncology, 2021, 05-01, Volume: 43, Issue:4

    Molecularly targeted therapy with MEK inhibitors has been increasingly incorporated into the treatment of pediatric low-grade gliomas, but this promising therapy is associated with distinctive and specific toxicities. Understanding life-threatening MEK inhibitor toxicities and their management is critical to MEK inhibitor safety, especially among young children. This report describes severe hyponatremia associated with trametinib in an infant with progressive low-grade glioma without underlying endocrine dysfunction, which recurred despite significant dose reduction. Therapy with an alternative MEK inhibitor, binimetinib, provided excellent tumor response without hyponatremia, suggesting that some toxicities may be avoided by changing MEK inhibitor agents within the same class.

    Topics: Antineoplastic Agents; Benzimidazoles; Glioma; Humans; Hyponatremia; Infant; Male; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2021
Discovery of Potent SARS-CoV-2 Inhibitors from Approved Antiviral Drugs via Docking and Virtual Screening.
    Combinatorial chemistry & high throughput screening, 2021, Volume: 24, Issue:3

    Coronavirus Disease 2019 (COVID-19) pandemic continues to threaten patients, societies and healthcare systems around the world. There is an urgent need to search for possible medications.. This article intends to use virtual screening and molecular docking methods to find potential inhibitors from existing drugs that can respond to COVID-19.. To take part in the current research investigation and to define a potential target drug that may protect the world from the pandemic of corona disease, a virtual screening study of 129 approved drugs was carried out which showed that their metabolic characteristics, dosages used, potential efficacy and side effects are clear as they have been approved for treating existing infections. Especially 12 drugs against chronic hepatitis B virus, 37 against chronic hepatitis C virus, 37 against human immunodeficiency virus, 14 anti-herpesvirus, 11 anti-influenza, and 18 other drugs currently on the market were considered for this study. These drugs were then evaluated using virtual screening and molecular docking studies on the active site of the (SARS-CoV-2) main protease (6lu7). Once the efficacy of the drug is determined, it can be approved for its in vitro and in vivo activity against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which can be beneficial for the rapid clinical treatment of patients. These drugs were considered potentially effective against SARS-CoV-2 and those with high molecular docking scores were proposed as novel candidates for repurposing. The N3 inhibitor cocrystallized with protease (6lu7) and the anti-HIV protease inhibitor Lopinavir were used as standards for comparison.. The results suggest the effectiveness of Beclabuvir, Nilotinib, Tirilazad, Trametinib and Glecaprevir as potent drugs against SARS-CoV-2 since they tightly bind to its main protease.. These promising drugs can inhibit the replication of the virus; hence, the repurposing of these compounds is suggested for the treatment of COVID-19. No toxicity measurements are required for these drugs since they were previously tested prior to their approval by the FDA. However, the assessment of these potential inhibitors as clinical drugs requires further in vivo tests of these drugs.

    Topics: Antiviral Agents; Binding Sites; Coronavirus 3C Proteases; Drug Evaluation, Preclinical; Drug Repositioning; Hepacivirus; Influenza A virus; Lopinavir; Molecular Docking Simulation; Pyridones; Pyrimidinones; SARS-CoV-2

2021
Successful Switch to Vemurafenib Plus Cobimetinib After Dabrafenib Plus Trametinib Toxicity in BRAF
    Clinical lung cancer, 2021, Volume: 22, Issue:1

    Topics: Adenocarcinoma of Lung; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Substitution; Humans; Imidazoles; Lung Neoplasms; Male; Middle Aged; Mutation; Oximes; Piperidines; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

2021
Dabrafenib and trametinib induced pancreatitis: a case report and review of the literature.
    Anti-cancer drugs, 2021, 02-01, Volume: 32, Issue:2

    Approximately 50% of melanomas are characterized by BRAF mutation (V600E in 90% of cases), that predicts more aggressive behaviour. This mutation is the target of dabrafenib, an anti-BRAF tyrosine-kinase inhibitor (TKI), that together with trametinib, anti-MEK TKI, is approved for first-line treatment of metastatic melanoma due to significant benefit in overall and progression-free survival. Most common treatment-related adverse events are pyrexia, chills, fatigue, rash, nausea, vomiting, and diarrhoea. This case report aims to present another less common adverse event of combined anti-BRAF and anti-MEK treatment. Our patient, after 4 months on target-therapy, experienced sudden deep abdominal pain. At the initial work-out at the emergency department, increase in serum lipase was detected and radiological findings were consistent with acute pancreatitis. Admitted to the hospital, other causes were ruled out and target-therapy was discontinued with symptoms improvement. Radiological and clinical follow-up was performed and a diagnosis of drug-induced pancreatitis was made. After few days of medical support with analgesia and antibiotic, the patient felt better and was discharged; target-therapy was permanently interrupted. Searching the literature, not so many cases of iatrogenic pancreatitis are described with this TKI combination, therefore, we have reported it as a rare but life-threatening adverse event that should be investigated whenever conceivable.

    Topics: Aged, 80 and over; Humans; Imidazoles; Male; Melanoma; Neoplasm Metastasis; Oximes; Pancreatitis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2021
Comment on: Langerhans cell histiocytosis with BRAF p.N486_P490del or MAP2K1 p.K57_G61del treated by the MEK inhibitor trametinib.
    Pediatric blood & cancer, 2021, Volume: 68, Issue:4

    Topics: Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Kinase 1; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
Next-generation sequencing-guided molecular-targeted therapy and immunotherapy for biliary tract cancers.
    Cancer immunology, immunotherapy : CII, 2021, Volume: 70, Issue:4

    Chemotherapy is a standard regimen for advanced or relapsed biliary tract cancer (BTC) with a 5-year overall survival (OS) rate of approximately 5% and a median OS of less than a year. Targeted therapies and immunotherapy aimed at providing more personalized treatments for BTCs have been tested. The objective of this study was to evaluate the effects of targeted therapy and immunotherapy on advanced BTC patients.. Twenty-four advanced/relapsed BTC patients were enrolled and examined with next-generation sequencing (NGS). Eight of them received NGS-guided targeted or immunotherapy, and the other 16 patients underwent routine chemotherapy. Comparison analysis of OS and objective response rate (ORR) was performed.. IDH1, BRCA2, MAP2K1, and BRAF (V600E) were the major actionable genes mutated in this cohort. Patients who received NGS-guided therapy exhibited higher OS (not achieved vs. 6.5 months, p < 0.001) and ORR (87.5% vs. 25%, p < 0.001) than those without targetable mutations and who received first-line chemotherapy. BTCs harboring mutations in IDH1, ATM/BRCA2, or MAP2K1/BRAF (V600E) received treatment with dasatinib, olaparib, or trametinib, respectively. Three of the patients had high tumor mutation burden (TMB-H) and were treated with immune-checkpoint inhibitors and chemotherapy. All these patients achieved complete response or partial response.. NGS-guided targeted therapy and immunotherapy are promising personalized therapies for advanced or relapsed BTCs. TMB is a useful biomarker for predicting immunotherapy efficacy.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Biomarkers, Tumor; Combined Modality Therapy; Dasatinib; Female; Follow-Up Studies; High-Throughput Nucleotide Sequencing; Humans; Immunotherapy; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Phthalazines; Piperazines; Prognosis; Prospective Studies; Pyridones; Pyrimidinones; Survival Rate

2021
Combined treatment with auranofin and trametinib induces synergistic apoptosis in breast cancer cells.
    Journal of toxicology and environmental health. Part A, 2021, 01-17, Volume: 84, Issue:2

    Auranofin is a gold complex used as an anti-rheumatic agent and may act as a potent anticancer drug against breast tumors. Trametinib is a specific mitogen-activated protein kinase inhibitor, approved for the treatment of metastatic melanoma. The aim of this study was to examine the synergistic effects of auranofin and trametinib on apoptosis in MCF-7 human breast cancer cells. The combination treatment inhibited cancer cell proliferation and induced cell cycle arrest at the sub-G1 phase and apoptosis via poly (ADP-ribose) polymerase cleavage and caspase-3/7 activation. It is noteworthy that this treatment significantly increased p38 mitogen-activated protein kinase (MAPK) phosphorylation to induce mitochondrial stress, subsequently promoting cancer cell apoptosis through release of apoptosis-inducing factor. Further data demonstrated that combined treatment significantly induced increase in nuclear translocation of AIF. These results indicated that activation of the p38 MAPK signaling pathway and mitochondrial apoptosis may contribute to the synergistic consequences in MCF-7 cells. Collectively, our data demonstrated that combined treatment with auranofin and trametinib exhibited synergistic breast cancer cell death and this combination might be utilized as a novel therapeutic strategy for breast cancer.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Auranofin; Breast Neoplasms; Cell Proliferation; Female; Humans; MCF-7 Cells; p38 Mitogen-Activated Protein Kinases; Pyridones; Pyrimidinones

2021
Discrepancy in responses to dabrafenib plus trametinib combination therapy in intracranial and extracranial metastases in melanoma patients.
    The Journal of dermatology, 2021, Volume: 48, Issue:2

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2021
Efficacy and safety of full-dose dabrafenib and trametinib combination therapy in a patient on hemodialysis with metastatic melanoma.
    International journal of dermatology, 2021, Volume: 60, Issue:4

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Renal Dialysis; Skin Neoplasms

2021
Simultaneous quantification of dabrafenib, hydroxy-dabrafenib and trametinib in human plasma by liquid chromatography-tandem mass spectrometry.
    Journal of pharmaceutical and biomedical analysis, 2021, Jan-30, Volume: 193

    A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of dabrafenib (DAB), its main metabolite hydroxy-dabrafenib (OHD) and trametinib (TRA) in human plasma has been developed and validated. After addition of internal standard (dabrafenib-d9), extraction was achieved after protein precipitation with acetonitrile containing 1 % (v/v) formic acid. Chromatographic separation was performed on an Accucore® C18 (2.1 × 50 mm; 2.6 μm) column using a gradient elution of water acidified with 0.1 % (v/v) formic acid (A) and acetonitrile containing 0.1 % (v/v) formic acid (B) at a flow rate of 500 μL/min. The calibration ranged from 10 to 2000 ng/mL for DAB and OHD and from 5 to 50 ng/mL for TRA. This method was validated with satisfactory results including good precision (intra- and inter-assay coefficient of variation from 2.0 %-14.9 %) and good accuracy (inter- and intra-day bias between -1.2 % and 10.9 %), as well as long term stability in unprocessed plasma at -20 °C. This newly proposed method is useful for clinical research purposes as well as therapeutic drug monitoring for patients with a Rapidly Accelerated Fibrosarcoma kinase B (BRAF)-mutated cancer.

    Topics: Chromatography, Liquid; Humans; Imidazoles; Oximes; Pyridones; Pyrimidinones; Reproducibility of Results; Tandem Mass Spectrometry

2021
A Novel Neoplastic Fusion Transcript,
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2021, 02-01, Volume: 27, Issue:3

    Luminal B breast tumors are more aggressive estrogen receptor-positive (ER. We performed large-scale RNA sequencing analysis to identify chimerical transcripts preferentially expressed in luminal B breast cancer. The lead candidate was validated by reverse transcription PCR in breast cancer tissues. The effects of inducible ectopic expression or genetic silencing were assessed by phenotypic assays such as MTS, transwell, and transendothelial migration assays, and by clonogenic assays to assess MEK inhibitor sensitivity. Subcellular fractionation, Western blots, and immunoprecipitation were performed to characterize the protein products and elucidate the engaged mechanisms.. This discovery sheds light on a new area of molecular pathobiology of luminal B tumors and implies potential new therapeutic opportunities for more aggressive breast tumors overexpressing this fusion.

    Topics: Breast; Breast Neoplasms; Cell Line, Tumor; Datasets as Topic; DNA-Binding Proteins; Drug Resistance, Neoplasm; Dyrk Kinases; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Oncogene Proteins, Fusion; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Pyridones; Pyrimidinones; RNA-Binding Proteins; RNA-Seq

2021
Serum soluble CD163 and proinflammatory chemokines may be biomarkers of the onset of adverse events in dabrafenib plus trametinib combination therapy for advanced melanoma.
    Dermatologic therapy, 2021, Volume: 34, Issue:1

    Various adverse events (AEs) have been reported to occur at a high rate in patients treated with dabrafenib plus trametinib (D + T) combination therapy. Among such AEs, the incidence of pyrexia was highest among the series of AEs in patients treated with D + T combination therapy. Although little is known about the mechanisms of pyrexia caused by D + T combination therapy, a recent report suggested that sCD163, as well as interferon-inducible chemokines (CXCL9, CXCL10, CXCL11), might correlate with pyrexia caused by encorafenib plus binimetinib combination therapy. In addition to these soluble factors, CXCL5 is a biomarker for predicting immune-related AEs in melanoma patients treated with nivolumab. From the above findings, we hypothesized that these soluble factors might also correlate with the onset of AEs in D + T combination therapy. The serum levels of sCD163 were increased in patients with pyrexia in parallel with their severity, whereas the serum levels of CXCL5 were increased in patients without pyrexia. Moreover, increased levels of CXCL9, CXCL10, and CXCL11 were prominent in patients with AEs over G2 levels. As these chemokines recruit Th1, Th17, and activated CD8+ T cells, increased serum levels of these chemokines might correlate with the positive feedback of inflammatory reactions related to AEs.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Chemokines; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2021
Pyrexia by COVID-19 in a patient treated with dabrafenib/trametinib therapy.
    The Journal of dermatology, 2021, Volume: 48, Issue:2

    Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; COVID-19; COVID-19 Nucleic Acid Testing; Diagnosis, Differential; Female; Fever; Humans; Imidazoles; Lung; Melanoma; Oximes; Pyridones; Pyrimidinones; RNA, Viral; SARS-CoV-2; Skin Neoplasms; Tomography, X-Ray Computed

2021
Widespread Repression of Gene Expression in Cancer by a Wnt/β-Catenin/MAPK Pathway.
    Cancer research, 2021, 01-15, Volume: 81, Issue:2

    Topics: Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Proliferation; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 4 or More Rings; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; Pyridones; Pyrimidinones; Tumor Cells, Cultured; Wnt1 Protein; Xenograft Model Antitumor Assays

2021
Comment on: Response to the BRAF/MEK inhibitors dabrafenib/trametinib in an adolescent with a BRAF V600E mutated anaplastic ganglioglioma intolerant to vemurafenib.
    Pediatric blood & cancer, 2021, Volume: 68, Issue:4

    Topics: Adolescent; Brain Neoplasms; Ganglioglioma; Humans; Imidazoles; Mitogen-Activated Protein Kinase Kinases; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

2021
Dabrafenib and trametinib therapy in an elderly patient with non-small cell lung cancer harboring the BRAF V600E mutation.
    Thoracic cancer, 2021, Volume: 12, Issue:2

    Dabrafenib and trametinib therapy for BRAF V600E-mutant non-small cell lung cancer (NSCLC) has demonstrated strong antitumor effects in clinical trials and has been approved for use in clinical practice. However, the efficacy and safety of this combination therapy in elderly patients remain unclear. An 86-year-old male patient, who had been diagnosed with lung adenocarcinoma with the BRAF V600E mutation, received dabrafenib and trametinib combination chemotherapy. The tumor shrunk rapidly; however, therapy was discontinued after 40 days because adverse events (hypoalbuminemia, peripheral edema, and pneumonia) developed. Although this targeted combination therapy seemed to cause relatively severe adverse events compared with single-agent targeted therapy in this "oldest old" elderly patient, the marked tumor shrinkage prolonged the patient's life and helped him to maintain a good general condition. Active targeted therapy may therefore be considered with appropriate drug dose reduction instead of conservative treatment, even if a patient is extremely old.

    Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
Trametinib and Hydroxychloroquine (HCQ) Combination Treatment in KRAS-Mutated Advanced Pancreatic Adenocarcinoma: Detailed Description of Two Cases.
    Journal of gastrointestinal cancer, 2021, Volume: 52, Issue:1

    Over the last decades, cytotoxic chemotherapy has been the cornerstone of metastatic pancreatic adenocarcinoma treatment. In late-stage disease, a range of treatment regimens still offers minor benefits. Molecular profiling studies have shown that pancreatic adenocarcinoma (PDAC) is a mutation-driven tumor type, with KRAS mutations found in approximately 90% of cases, which could partially explain the resistance to chemotherapy. Preclinical data on selective targeting of a downstream point of the RAF-MEK-ERK pathway with a MEK inhibitor along with the concurrent use of an autophagy inhibitor such as hydroxychloroquine appears to be one alternative approach to overcome resistance and inhibit cell proliferation.. We herein aim to investigate the rationale of autophagy inhibitors use and describe the outcomes of patients who received this experimental treatment.. Two patients have received this experimental regimen from January 2020 to the present date, achieving disease stabilization that is clinically meaningful, considering the chemoresistance scenario of the included patients.. Our real-life data regarding KRAS-mutated PDAC patients who received treatment with the MEK inhibitor trametinib combined with hydroxychloroquine after experiencing disease progression are consistent with the preclinical data, pointing to the clinical benefits of this regimen.

    Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Autophagy; CA-19-9 Antigen; Carcinoma, Pancreatic Ductal; Disease Progression; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Humans; Hydroxychloroquine; Male; MAP Kinase Signaling System; Middle Aged; Mutation; Neoplasm Staging; Pancreas; Pancreatic Neoplasms; Positron Emission Tomography Computed Tomography; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Treatment Outcome

2021
Re-irradiation with concurrent BRAF and MEK inhibitor therapy.
    Pediatric blood & cancer, 2021, Volume: 68, Issue:5

    Topics: Adolescent; Brain Neoplasms; Chemoradiotherapy; Fatal Outcome; Glioma; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Re-Irradiation

2021
Dabrafenib-trametinib combination therapy re-challenge in advanced BRAF
    European journal of cancer (Oxford, England : 1990), 2021, Volume: 143

    Topics: Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Lung Neoplasms; Mitogen-Activated Protein Kinase Kinases; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
Complete Resolution of Bilateral Choroidal Metastases of Cutaneous Melanoma With Combined Targeted Therapy.
    Retina (Philadelphia, Pa.), 2021, Mar-01, Volume: 41, Issue:3

    Topics: Choroid; Choroid Neoplasms; Drug Therapy, Combination; Follow-Up Studies; Humans; Imidazoles; Immunotherapy; Injections, Intralesional; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Tomography, Optical Coherence

2021
Combination therapy of dabrafenib plus trametinib in patients with BRAF
    Hepatobiliary & pancreatic diseases international : HBPD INT, 2021, Volume: 20, Issue:5

    Topics: Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Humans; Imidazoles; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
MEK Inhibition Reverses Aberrant Signaling in Melanoma Cells through Reorganization of NRas and BRAF in Self Nanoclusters.
    Cancer research, 2021, 03-01, Volume: 81, Issue:5

    Hotspot mutations of the oncogenes BRAF and NRas are the most common genetic alterations in cutaneous melanoma. Still, the nanoscale organization and signal coupling of these proteins remain incompletely understood, particularly upon expression of oncogenic NRas mutants. Here we employed single-molecule localization microscopy to study the nanoscale organization of NRas and BRAF at the plasma membrane (PM) of melanoma cells. NRas and BRAF resided in self-clusters that did not associate well in resting cells. In EGF-activated cells, NRas clusters became more diffused while overall protein levels at the PM increased; thus allowing enhanced association of NRas and BRAF and downstream signaling. In multiple melanoma cell lines, mutant NRas resided in more pronounced self-clusters relative to wild-type (WT) NRas yet associated more with the clustered and more abundant BRAF. In cells resistant to trametinib, a clinical MEK inhibitor (MEKi), a similar coclustering of NRas and BRAF was observed upon EGF activation. Strikingly, treatment of cells expressing mutant NRas with trametinib reversed the effect of mutant NRas expression by restoring the nonoverlapping self-clusters of NRas and BRAF and by reducing their PM levels and elevated pERK levels caused by mutant NRas. Our results indicate a new mechanism for signal regulation of NRas in melanoma through its nanoscale dynamic organization and a new mechanism for MEKi function in melanoma cells carrying NRas mutations but lacking MEK mutations. SIGNIFICANCE: Nanoscale dynamic organization of WT and mutant NRas relative to BRAF serves as a regulatory mechanism for NRas signaling and may be a viable therapeutic target for its sensitivity to MEKi.

    Topics: Cell Line, Tumor; Cell Membrane; Epidermal Growth Factor; Extracellular Signal-Regulated MAP Kinases; GTP Phosphohydrolases; Humans; MAP Kinase Kinase 1; Melanoma; Melanoma, Cutaneous Malignant; Membrane Proteins; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Signal Transduction; Single Molecule Imaging; Skin Neoplasms

2021
Dabrafenib plus trametinib combination therapy triggered onset of pustulosis palmaris et plantaris in a patient with advanced cutaneous melanoma.
    The Journal of dermatology, 2021, Volume: 48, Issue:3

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Psoriasis; Pyridones; Pyrimidinones; Skin Neoplasms

2021
Agminated benign vascular tumour successfully treated with trametinib.
    The British journal of dermatology, 2021, Volume: 184, Issue:6

    Topics: Humans; Neoplasms, Vascular Tissue; Pyridones; Pyrimidinones; Vascular Neoplasms

2021
BRAF L597K mutation: an opportunity to treat.
    Dermatology online journal, 2021, Jan-15, Volume: 27, Issue:1

    The outcomes of patients with metastatic melanoma (MM) have significantly improved after the introduction of BRAF-specific inhibitors. Herein is reported a patient with MM and non-V600-BRAF mutation who responded to iBRAF/iMEK therapy. In July 2014, a 63-year-old man presented with a 4.1mm-thick V600E-BRAF wild type melanoma on the back. Metastases were identified in one sentinel node and two of 11 subsequently excised lymph nodes, with no signs of distant metastatic disease. In September 2017, lung metastasis was observed and pembrolizumab was started. Progressive disease was apparent at cycle 10 and therapy was switched to ipilimumab. After four cycles, an asymmetric response was observed. In November 2017, next generation sequencing genomic profiling disclosed a rare L597K-BRAF mutation and vemurafenib plus cobimetinib therapy was initiated in January 2018. Seven days after treatment start, a remarkable clinical improvement was observed. In April 2018, the patient achieved partial response, which was sustained until October 2018. Cases of patients with non-V600-BRAF mutations responding to iBRAF/iMEK therapy have been reported over the last years. To the best of our knowledge, this is the first case reporting response to combined iBRAF/iMEK therapy in a patient with metastatic melanoma harboring L597K mutation.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Back; Dacarbazine; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

2021
Dramatic clinical response to dabrafenib plus trametinib in anaplastic thyroid carcinoma and the challenges faced during the COVID-19 pandemic.
    Archives of endocrinology and metabolism, 2021, Nov-01, Volume: 65, Issue:2

    Anaplastic thyroid carcinoma is the rarest tumor of the thyroid gland, representing less than 2% of clinically recognized thyroid cancers. Typically, it has an extremely rapid onset, fatal outcomes in most cases, and a median overall survival of 3 to 10 months despite aggressive multidisciplinary management. The presence of targetable mutations in anaplastic thyroid carcinoma patients is an opportunity for treatment when conventional therapeutics approaches are not effective, a frequent situation in the majority of patients. We present our experience in the management of a patient with unresectable anaplastic thyroid cancer who had a remarkable and rapid response to treatment with dabrafenib and trametinib during the COVID-19 pandemic. After four weeks of dabrafenib 150 mg twice daily plus trametinib 2 mg daily, he showed a dramatic reduction of the cervical mass around 90%. Nearly eight weeks under treatment with dabrafenib plus trametinib, the patient remains with minimal locoregional disease without distant metastases.

    Topics: Antineoplastic Combined Chemotherapy Protocols; COVID-19; Humans; Imidazoles; Male; Mutation; Oximes; Pandemics; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; SARS-CoV-2; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

2021
Circulating tumour DNA in patients with melanoma receiving targeted therapy.
    The Lancet. Oncology, 2021, Volume: 22, Issue:3

    Topics: Circulating Tumor DNA; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones

2021
Pneumatosis intestinalis in a radioactive iodine-refractory metastasic thyroid papillary carcinoma with BRAF
    Journal of medical case reports, 2021, Mar-02, Volume: 15, Issue:1

    Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors.. A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAF. This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib-trametinib. Conservative treatment is feasible if there are no abdominal symptoms.

    Topics: Emphysema; Female; Humans; Imidazoles; Intestinal Diseases; Iodine Radioisotopes; Middle Aged; Oximes; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skull Base Neoplasms; Thyroid Cancer, Papillary; Thyroid Neoplasms

2021
Targeted Therapy Given after Anti-PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity.
    Cancer immunology research, 2021, Volume: 9, Issue:5

    Immunotherapy (IT) and targeted therapy (TT) are both effective against melanoma, but their combination is frequently toxic. Here, we investigated whether the sequence of IT (anti-PD-1)→ TT (ceritinib-trametinib or dabrafenib-trametinib) was associated with improved antitumor responses in mouse models of

    Topics: Animals; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Disease Models, Animal; Female; Imidazoles; Immunotherapy; Melanoma; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Molecular Targeted Therapy; Monomeric GTP-Binding Proteins; Mutation; Oximes; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones; Skin Neoplasms; Sulfones; T-Lymphocytes, Regulatory

2021
A case of multi-metastatic melanoma with RAF1 fusion: a surprising response to anti-MEK therapy.
    European journal of cancer (Oxford, England : 1990), 2021, Volume: 147

    Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Biomarkers, Tumor; Female; Gene Fusion; Humans; Immune Checkpoint Inhibitors; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2021
Evaluating Melanoma Viability and Proliferation in 3D Microenvironments.
    Methods in molecular biology (Clifton, N.J.), 2021, Volume: 2265

    Researchers often aim to incorporate microenvironmental variables such as the dimensionality and composition of the extracellular matrix into their cell-based assays. A technical challenge created by introduction of these variables is quantification of single-cell measurements and control of environmental reproducibility. Here, we detail a methodology to quantify viability and proliferation of melanoma cells in 3D collagen-based culture platforms by automated microscopy and 3D image analysis to yield robust, high-throughput results of single-cell responses to drug treatment.

    Topics: Antineoplastic Agents; Cell Culture Techniques; Cell Proliferation; Cell Survival; Collagen; Image Processing, Computer-Assisted; Imidazoles; Melanoma; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Single-Cell Analysis; Spheroids, Cellular

2021
MX2 mediates establishment of interferon response profile, regulates XAF1, and can sensitize melanoma cells to targeted therapy.
    Cancer medicine, 2021, Volume: 10, Issue:8

    MX2 is an interferon inducible gene that is mostly known for its antiviral activity. We have previously demonstrated that MX2 is also associated with the tumorigenesis process in melanoma. However, it remains unknown which molecular mechanisms are regulated by MX2 in response to interferon signaling in this disease. Here, we report that MX2 is necessary for the establishment of an interferon-induced transcriptional profile partially through regulation of STAT1 phosphorylation and other interferon-related downstream factors, including proapoptotic tumor suppressor XAF1. MX2 and XAF1 expression tightly correlate in both cultured melanoma cell lines and in patient-derived primary and metastatic tumors, where they also are significantly related with survival. MX2 mediates IFN growth-inhibitory signals in both XAF1 dependent and independent ways and in a cell type and context-dependent manner. Higher MX2 expression renders melanoma cells more sensitive to targeted therapy drugs such as vemurafenib and trametinib; however, this effect is XAF1 independent. In summary, we uncovered a new mechanism in the complex regulation of interferon signaling in melanoma that can influence both survival and response to therapy.

    Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers, Tumor; Cell Proliferation; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Interferons; Melanoma; Molecular Targeted Therapy; Myxovirus Resistance Proteins; Phosphorylation; Pyridones; Pyrimidinones; STAT1 Transcription Factor; Tumor Cells, Cultured

2021
Extreme elevation of acute phase reactants and shock secondary to dabrafenib-trametinib.
    Melanoma research, 2021, 06-01, Volume: 31, Issue:3

    The emerging role of BRAF and MEK tyrosine-kinase inhibitors has shown new opportunities of treatment for patients with advanced melanoma and BRAF mutations. Its use is associated with some toxicities, as pyrexia, that clinicians may not be familiarized with. We present the case of a patient diagnosed with stage IV melanoma BRAF Val600E mutated who was started on dabrafenib and trametinib and developed three severe episodes of fever, hypotension and acute phase reactants elevation during the first 3 months of therapy, in the absence of microbiological demonstration of infection. The episodes were initially managed as a septic shock with broad-spectrum antibiotics and vasoactive drugs, while treatment with dabrafenib and trametinib was withheld. After two subsequent dose reduction of dabrafenib, the patient did not experience new episodes of fever.

    Topics: Acute-Phase Proteins; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Male; Middle Aged; Oximes; Pyridones; Pyrimidinones; Shock; Survival Analysis

2021
Trametinib for orbital plexiform neurofibromas in young children with neurofibromatosis type 1.
    Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 2021, Volume: 37, Issue:6

    Plexiform neurofibromas (PNF) in neurofibromatosis type 1 (NF1) are usually diagnosed in childhood and can grow rapidly during this period. In 10% of patients, PNF involve the orbital-periorbital area and may cause visual problems including glaucoma, visual loss from amblyopia (deprivational, strabismic, or refractive), optic nerve compression, or keratopathy. Ptosis, proptosis, and facial disfigurement lead to social problems and decreased self-esteem. Complete surgical removal involves significant risks and mutilation, and regrowth after debulking is not uncommon. Inhibitors of the RAS/MAPK pathway have recently been investigated for their activity in PNF. We administered the oral MEK inhibitor trametinib to five young children with NF1 and PNF of the orbital area, with visual compromise and progressive tumor growth; and followed them clinically and by volumetric MRI.. Treatment was initiated at a mean age of 26.8 months (SD ± 12.8) and continued for a median 28 months (range 16-51). Doses were 0.025 mg/kg/day for children aged > 6 years and 0.032 mg/kg/day for those aged < 6 years.. Volumetric MRI measurements showed a reduction of 2.9-33% at 1 year after treatment initiation, with maximal reductions of 44% and 49% in two patients, at 44 and 36 months, respectively. No change in visual function was recorded during treatment. One child reported decreased orbital pain after 2 weeks; and another, with involvement of the masseters, had increased ability to chew food. Toxicities were mostly to skin and nails, grades 1-2.. Trametinib can decrease tumor size in some young children with orbital PNF and may prevent progressive disfigurement.

    Topics: Child; Child, Preschool; Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Pyridones; Pyrimidinones

2021
Effect of Metformin in Combination With Trametinib and Paclitaxel on Cell Survival and Metastasis in Melanoma Cells.
    Anticancer research, 2021, Volume: 41, Issue:3

    Despite clinical benefit from treatment with dabrafenib and trametinib in melanoma patients with BRAF mutations, half relapse within months and one-third are unresponsive to treatment. We evaluated the anticancer potential of metformin in combination with trametinib plus paclitaxel, against four melanoma cell lines.. Metformin with trametinib and paclitaxel was tested for effects on cell viability, signaling molecules in MAPK and mTOR pathways, factors involved in epithelial-mesenchymal transition (EMT), and cell motility.. The combination of metformin with trametinib and paclitaxel showed differential growth inhibitory effects; synergistic effects were observed in a cell line in which metformin suppresses ERK activity, whereas the combination showed antagonistic effects in a cell line with metformin-induced ERK activation. Trametinib or paclitaxel increased the expression of EMT regulators and melanoma cell motility, which were suppressed by combining metformin with trametinib and paclitaxel.. The combined treatment of metformin with trametinib and paclitaxel showed divergent effects on melanoma cell viability. Metformin might be useful as a potential adjuvant against cell proliferation and metastatic activity in melanoma patients.

    Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Drug Synergism; Epithelial-Mesenchymal Transition; Humans; Melanoma; Metformin; Mutation; Paclitaxel; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Signal Transduction; Skin Neoplasms

2021
Methiothepin Increases Chemotherapy Efficacy against Resistant Melanoma Cells.
    Molecules (Basel, Switzerland), 2021, Mar-26, Volume: 26, Issue:7

    We previously reported that methiothepin, a small molecule known as a nonselective serotonin 5-HT receptor antagonist, inhibited the doxorubicin efflux activity of the Hedgehog receptor Ptch1 and enhanced the cytotoxic, pro-apoptotic, anti-proliferative, and anti-clonogenic effects of doxorubicin on adrenocortical carcinoma cells. Here, we show that methiothepin also inhibits doxorubicin efflux and increases doxorubicin cytotoxicity in melanoma cells which endogenously overexpress Ptch1. Melanoma patients having the BRAF

    Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Drug Resistance, Neoplasm; Humans; Melanoma; Methiothepin; Patched-1 Receptor; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

2021
Multimodal treatments and outcomes for anaplastic thyroid cancer before and after tyrosine kinase inhibitor therapy: a real-world experience.
    European journal of endocrinology, 2021, May-06, Volume: 184, Issue:6

    Anaplastic thyroid cancer (ATC) has dismal prognosis and there is no effective treatment. We aimed to evaluate the efficacy of tyrosine kinase inhibitor (TKI) therapy in real-world clinic and to suggest the most effective treatment modality according to the combination of treatments.. This retrospective study evaluated clinical outcomes and cause of death with multimodal treatments in patients with ATC at Samsung Medical Center.. A total of 120 patients received anti-cancer treatment for ATC. Seventy-seven (64.2%) patients underwent surgery, 64 (53.3%) received radiotherapy, 29 (24.2%) received cytotoxic chemotherapy, and 19 (15.8%) received TKI therapy. In the TKI therapy group, eight achieved partial response (three with lenvatinib and five with dabrafenib plus trametinib), and two patients with lenvatinib showed stable disease. Median progression-free survival (PFS) of the TKI therapy group was 2.7 months (range: 0.1-12.7) and their median overall survival (OS) was 12.4 months (range: 1.7-47.7). Patients who received surgery or radiotherapy for local control showed superior OS than those who did not. In a multivariate analysis, surgery, TKI therapy, younger age, and no distant metastasis were associated with favorable OS. The combination of surgery, radiotherapy, and TKI therapy (median OS: 34.3 months, 6-month survival rates: 77.8%) was the most effective. Compared to the era without TKI therapy, distant metastasis has recently become the major cause of death in ATC over airway problems.. Multimodality treatment including TKI therapy demonstrated prolonged survival with dabrafenib plus trametinib as the most effective therapeutic option demonstrated for BRAF mutant ATC patients.

    Topics: Age Factors; Aged; Antineoplastic Agents; Combined Modality Therapy; Female; Humans; Imidazoles; Male; Middle Aged; Oximes; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Quinolines; Retrospective Studies; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

2021
Anti-relapse effect of trametinib on a local minimal residual disease neuroblastoma mouse model.
    Journal of pediatric surgery, 2021, Volume: 56, Issue:7

    We reported the in vitro and in vivo anti-tumor effects of trametinib, an MEK inhibitor, on neuroblastoma. However, long-term trametinib administration for bulky tumors failed to prevent local relapse. In this study, we established a local minimal residual disease (L-MRD) model to develop an optimal clinical protocol.. We prepared an l-MRD model by implanting neuroblastoma cells (SK-N-AS) into the renal capsule of nude mice with total tumorectomy or sham operation 14 days later. These mice received post-operative administration of trametinib or vehicle for eight weeks. Relapse was measured once weekly. Flow cytometry was performed with SK-N-AS cells treated by trametinib.. Tumorectomy+trametinib dramatically suppressed relapse, and all mice survived during trametinib administration, while other treatments failed to suppress relapse. The survival rates for other groups were 20% in sham+trametinib, 17% in tumorectomy+vehicle, and 0% in sham+vehicle. Relapse occurred in the tumorectomy+trametinib group after withdrawal of trametinib administration. Flow cytometry revealed G1 arrest in SK-N-AS cells treated with trametinib.. These findings suggested that trametinib was able to suppress relapse from minimal residual tumor cells. Therefore, we propose that trametinib be administered as an option for maintenance therapy after surgical and chemotherapeutic treatments for neuroblastoma in future clinical protocols.

    Topics: Animals; Cell Line, Tumor; Mice; Mice, Nude; Neoplasm Recurrence, Local; Neoplasm, Residual; Neuroblastoma; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2021
Early response in phosphorylation of ribosomal protein S6 is associated with sensitivity to trametinib in colorectal cancer cells.
    Laboratory investigation; a journal of technical methods and pathology, 2021, Volume: 101, Issue:8

    Mutations in RAS or BRAF are associated with poor prognosis and resistance to epidermal growth factor receptor (EGFR)-targeted therapy in colorectal cancer (CRC). Despite their common ability to activate downstream genes such as MEK and ERK, the therapeutic benefit of MEK inhibitors for patients with RAS/BRAF mutant CRC is limited, highlighting the need for biomarkers to predict the efficacy of MEK inhibition. Previously, we reported that a change in phosphorylation of ribosomal protein S6 (pS6) after MEK inhibition was significantly associated with sensitivity to MEK inhibition in gastric cancer cells. Here, we investigated the value of the response in pS6 for predicting the efficacy of trametinib, a MEK inhibitor, in patients with RAS/BRAF mutant CRC using patient-derived CRC organoids. We found that a subset of CRC cell lines and organoids were sensitive to trametinib. The change in phosphorylated ERK, a downstream molecule of the RAS/RAF/MEK pathway, was not significantly associated with trametinib sensitivity. On the other hand, only those with sensitivity showed a reduction of pS6 levels in response to trametinib. The change in pS6 after trametinib treatment was detectable by Western blotting, immunohistochemistry or immunocytochemistry. We also demonstrated an impact of MEK inhibition on pS6 in vivo using a xenograft model. Our data suggest that, in combination with patient-derived organoids, immunostaining-based detection of pS6 could be useful for prediction of trametinib sensitivity.

    Topics: Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Cell Line, Tumor; Colorectal Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Male; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Ribosomal Protein S6

2021
Combined VEGFR and MAPK pathway inhibition in angiosarcoma.
    Scientific reports, 2021, 04-30, Volume: 11, Issue:1

    Angiosarcoma is an aggressive malignancy of endothelial cells that carries a high mortality rate. Cytotoxic chemotherapy can elicit clinical responses, but the duration of response is limited. Sequencing reveals multiple mutations in angiogenesis pathways in angiosarcomas, particularly in vascular endothelial growth factor (VEGFR) and mitogen-activated protein kinase (MAPK) signaling. We aimed to determine the biological relevance of these pathways in angiosarcoma. Tissue microarray consisting of clinical formalin-fixed paraffin embedded tissue archival samples were stained for phospho- extracellular signal-regulated kinase (p-ERK) with immunohistochemistry. Angiosarcoma cell lines were treated with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, pan-VEGFR inhibitor cediranib, or combined trametinib and cediranib and viability was assessed. Reverse phase protein array (RPPA) was performed to assess multiple oncogenic protein pathways. SVR angiosarcoma cells were grown in vivo and gene expression effects of treatment were assessed with whole exome RNA sequencing. MAPK signaling was found active in over half of clinical angiosarcoma samples. Inhibition of MAPK signaling with the MEK inhibitor trametinib decreased the viability of angiosarcoma cells. Combined inhibition of the VEGF and MAPK pathways with cediranib and trametinib had an additive effect in in vitro models, and a combinatorial effect in an in vivo model. Combined treatment led to smaller tumors than treatment with either agent alone. RNA-seq demonstrated distinct expression signatures between the trametinib treated tumors and those treated with both trametinib and cediranib. These results indicate a clinical study of combined VEGFR and MEK inhibition in angiosarcoma is warranted.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Hemangiosarcoma; Humans; MAP Kinase Signaling System; Mice; Mice, Nude; Prognosis; Pyridones; Pyrimidinones; Quinazolines; Transcriptome; Tumor Cells, Cultured; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

2021
Trametinib therapy for children with neurofibromatosis type 1 and life-threatening plexiform neurofibroma or treatment-refractory low-grade glioma.
    Cancer medicine, 2021, Volume: 10, Issue:11

    To describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib.. We report on six patients with NF-1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively.. Subjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4-28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life-threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1-2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy.. Trametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF-1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients.

    Topics: Adolescent; Antineoplastic Agents; Brain Neoplasms; British Columbia; Child; Child, Preschool; Compassionate Use Trials; Dermatitis, Atopic; Drug Resistance, Neoplasm; Female; Glioma; Humans; Infant; Male; Neurofibroma, Plexiform; Neurofibromatosis 1; Paronychia; Pyridones; Pyrimidinones; Retrospective Studies; Treatment Outcome

2021
Cardiovascular adverse events associated with BRAF versus BRAF/MEK inhibitor: Cross-sectional and longitudinal analysis using two large national registries.
    Cancer medicine, 2021, Volume: 10, Issue:12

    Cardiovascular adverse events (CVAEs) associated with BRAF inhibitors alone versus combination BRAF/MEK inhibitors are not fully understood.. This study included all adult patients who received BRAF inhibitors (vemurafenib, dabrafenib, encorafenib) or combinations BRAF/MEK inhibitors (vemurafenib/cobimetinib; dabrafenib/trametinib; encorafenib/binimetinib). We utilized the cross-sectional FDA's Adverse Events Reporting System (FAERS) and longitudinal Truven Health Analytics/IBM MarketScan database from 2011 to 2018. Various CVAEs, including arterial hypertension, heart failure (HF), and venous thromboembolism (VTE), were studied using adjusted regression techniques.. In FAERS, 7752 AEs were reported (40% BRAF and 60% BRAF/MEK). Median age was 60 (IQR 49-69) years with 45% females and 97% with melanoma. Among these, 567 (7.4%) were cardiovascular adverse events (mortality rate 19%). Compared with monotherapy, combination therapy was associated with increased risk for HF (reporting odds ratio [ROR] = 1.62 (CI = 1.14-2.30); p = 0.007), arterial hypertension (ROR = 1.75 (CI = 1.12-2.89); p = 0.02) and VTE (ROR = 1.80 (CI = 1.12-2.89); p = 0.02). Marketscan had 657 patients with median age of 53 years (IQR 46-60), 39.3% female, and 88.7% with melanoma. There were 26.2% CVAEs (CI: 14.8%-36%) within 6 months of medication start in those receiving combination therapy versus 16.7% CVAEs (CI: 13.1%-20.2%) among those receiving monotherapy. Combination therapy was associated with CVAEs compared to monotherapy (adjusted HR: 1.56 (CI: 1.01-2.42); p = 0.045).. In two independent real-world cohorts, combination BRAF/MEK inhibitors were associated with increased CVAEs compared to monotherapy, especially HF, and hypertension.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Cardiovascular Diseases; Colonic Neoplasms; Cross-Sectional Studies; Female; Heart Failure; Humans; Hypertension; Imidazoles; Lung Neoplasms; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Registries; Regression Analysis; Skin Neoplasms; Sulfonamides; Vemurafenib; Venous Thromboembolism; Young Adult

2021
Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia.
    Leukemia, 2021, Volume: 35, Issue:12

    Mutations in SET-binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. While some mechanisms for SETBP1-driven oncogenesis have been established, it remains unclear how SETBP1 specifically modulates the biology of Ras-driven leukemias. In this study, we found that when co-expressed with Ras pathway mutations, SETBP1 promoted oncogenic transformation of murine bone marrow in vitro and aggressive myeloid leukemia in vivo. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways. SETBP1 also enhances NRAS-driven phosphorylation of MAPK proteins. Cells expressing NRAS and SETBP1 are sensitive to inhibitors of the MAPK pathway, and treatment with the MEK inhibitor trametinib conferred a survival benefit in a mouse model of NRAS/SETBP1-mutant disease. Our data demonstrate that despite driving enhanced MAPK signaling, SETBP1-mutant cells remain susceptible to trametinib in vitro and in vivo, providing encouraging preclinical data for the use of trametinib in SETBP1-mutant disease.

    Topics: Animals; Bone Marrow; Carrier Proteins; Cells, Cultured; Disease Models, Animal; GTP Phosphohydrolases; Humans; Leukemia, Myelomonocytic, Juvenile; MAP Kinase Signaling System; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mutation; Nuclear Proteins; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction

2021
Gastrointestinal perforation following dabrafenib and trametinib administration in non-small cell lung carcinoma with BRAF V600E mutation: a case report and literature review.
    Investigational new drugs, 2021, Volume: 39, Issue:6

    Gastrointestinal perforation related to mitogen-activated protein kinase kinase (MEK) inhibitors has been reported previously; however, there has been no case report of such a condition in patients with non-small cell lung cancer (NSCLC). Herein, we report a case of small intestinal perforation secondary to dabrafenib and trametinib administration, but not related to tumor regression. A 62-year-old man with non-small cell lung cancer harboring BRAF V600E mutation was treated with dabrafenib and trametinib. Four months after the initiation of treatment, a small intestinal perforation was diagnosed. Dabrafenib and trametinib rechallenge was performed after gastrointestinal perforation. The patient responded well to therapy and did not experience recurrence of gastrointestinal perforation. To the best of our knowledge, this is the first report of gastrointestinal perforation in a patient with NSCLC treated with a MEK inhibitor. The mechanism and risk factors of trametinib-induced perforation are currently unknown. Physicians should be aware of such severe gastrointestinal side effects of trametinib.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Intestinal Perforation; Lung Neoplasms; Male; Middle Aged; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells.
    Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2021, Volume: 8, Issue:10

    Topics: Amides; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Synergism; Female; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mice; Mice, Inbred BALB C; Nuclear Proteins; Protein Kinase Inhibitors; Pyrazoles; Pyridones; Pyrimidinones; Ribose; Ribosomal Proteins; Survival Rate; Up-Regulation; Xenograft Model Antitumor Assays

2021
Anti-PD-1 in Combination With Trametinib Suppresses Tumor Growth and Improves Survival of Intrahepatic Cholangiocarcinoma in Mice.
    Cellular and molecular gastroenterology and hepatology, 2021, Volume: 12, Issue:3

    Intrahepatic cholangiocarcinoma (iCCA) accounts for a fraction of primary liver cancers but has a 5-year survival rate of only 10%. Immune checkpoint inhibitors are effective in treating many solid cancers, but immune checkpoint inhibitor monotherapy has no clear benefit in iCCA. Mitogen-activated kinase (MEK) inhibitors, such as trametinib, have shown promising results in preclinical studies for iCCA by inhibiting cell proliferation and modifying the tumor microenvironment. This study aimed to show the potential benefit of combining trametinib with anti-programmed cell death protein 1 (PD-1) therapy in different iCCA mouse models.. Here, we assessed the in vitro cytotoxicity of trametinib in mouse (SB1 and LD-1) and human (EGI-1) cholangiocarcinoma cell lines. We examined the efficacy of single-agent trametinib, anti-PD-1, and a combination of both in subcutaneous, orthotopic, and plasmid-induced iCCA mouse models. Flow cytometry analysis was used to elucidate changes in the tumor immune microenvironment upon treatment. Whole-exome sequencing (WES) was performed on the SB1 tumor cell line to correlate this preclinical model with iCCAs in patients.. Trametinib reduced tumor cell growth of SB1, LD-1, and EGI-1 tumor cells in vitro. Trametinib treatment led to up-regulation of major histocompatibility complex (MHC-I) and programmed cell death ligand 1 (PD-L-1) (programmed cell death ligand 1) on tumor cells in vitro. The combination of trametinib and anti-PD-1 reduced tumor burden in several iCCA tumor models and improved survival in SB1 tumor-bearing mice compared with either agent alone. Immunoprofiling of tumor-bearing mice showed an increase of hepatic effector memory CD8. Altogether, our study shows that trametinib improves the immunogenicity of tumor cells by up-regulating MHC-I surface expression. The combination with anti-PD-1 results in optimal treatment efficacy for iCCA. WES of SB1 cells suggests that KRAS wild-type iCCAs also respond to this combination therapy.

    Topics: Animals; Bile Duct Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cholangiocarcinoma; Drug Synergism; Exome Sequencing; Female; High-Throughput Nucleotide Sequencing; Humans; Immune Checkpoint Inhibitors; Mice; Programmed Cell Death 1 Receptor; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2021
Anti-tumor effect of trametinib in bladder cancer organoid and the underlying mechanism.
    Cancer biology & therapy, 2021, 06-03, Volume: 22, Issue:5-6

    Bladder cancer (BC), a main neoplasm of urinary tract, is usually inoperable and unresponsive to chemotherapy. As a novel experimental model for muscle-invasive BC, we previously established a culture method of dog BC organoids. In the present study, the detailed in vitro and in vivo anti-tumor effects of trametinib were investigated by using this model. In each BC organoid strain, epidermal growth factor receptor (EGFR)/ERK signaling was upregulated compared with normal bladder cells. Trametinib even at a low concentration inhibited the cell viability of BC organoids and the activation of ERK through decreasing expression of c-Myc, ELK1, SIK1, and PLA2G4A. Trametinib arrested cell cycle of BC with few apoptosis. Dual treatment of BC organoids with trametinib and YAP inhibitor, verteporfin extremely inhibited the cell viability with apoptosis induction. Moreover, trametinib induced basal to luminal differentiation of BC organoids by upregulating luminal markers and downregulating basal ones. In vivo, trametinib decreased the tumor growth of BC organoids in mice and the xenograft-derived organoids from trametinib-administered mice showed enhanced sensitivity to carboplatin due to MSH2 upregulation. Our data suggested a new strategy of trametinib-YAP inhibitor or trametinib-carboplatin combination as a promising treatment of BC.

    Topics: Animals; Cell Line, Tumor; Cell Proliferation; Dogs; Mice; Organoids; Pyridones; Pyrimidinones; Urinary Bladder Neoplasms

2021
Dabrafenib and trametinib exposure-efficacy and tolerance in metastatic melanoma patients: a pharmacokinetic-pharmacodynamic real-life study.
    Cancer chemotherapy and pharmacology, 2021, Volume: 88, Issue:3

    Dabrafenib plus trametinib combination has greatly improved survival in BRAFV600. BRAFV600. Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4 months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3 n = 10, G4 n = 0). In univariate analysis, median dabrafenib C. In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in BRAFV600

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bayes Theorem; Drug Monitoring; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Oximes; Progression-Free Survival; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

2021
The Combination of Trametinib, a MEK Inhibitor, and Temsirolimus, an mTOR Inhibitor, Radiosensitizes Lung Cancer Cells.
    Anticancer research, 2021, Volume: 41, Issue:6

    We evaluated the radiosensitizing effect of the combination treatment of trametinib, a MEK inhibitor, and temsirolimus, an mTOR inhibitor, on non-small-cell lung carcinoma (NSCLC) cells.. The effects of combining trametinib and temsirolimus with radiation in NSCLC cell lines were evaluated using clonogenic survival and apoptosis assays. DNA double-strand breaks and cell cycle distribution were analyzed using flow cytometry. Tumor volume was measured to determine the radiosensitivity in lung cancer xenograft models.. The combination of trametinib and temsirolimus can enhance lung cancer radiosensitivity in vitro and in vivo.

    Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; DNA Damage; Drug Therapy, Combination; Humans; Lung Neoplasms; MAP Kinase Kinase Kinases; Pyridones; Pyrimidinones; Radiation Tolerance; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

2021
Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2021, 08-15, Volume: 27, Issue:16

    Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells.. We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated. B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.

    Topics: Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2021
Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis.
    Journal of Zhejiang University. Science. B, 2021, Jun-15, Volume: 22, Issue:6

    Dysregulated crosstalk between different signaling pathways contributes to tumor development, including resistance to cancer therapy. In the present study, we found that the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib failed to suppress the proliferation of PANC-1 and MGC803 cells by activating the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, while the JAK2 inhibitor fedratinib failed to inhibit the growth of the PANC-1 cells upon stimulation of extracellular signal-regulated kinase (ERK) signaling. In particular, the most prominent enhancement of the anti-proliferative effect resulted from the concurrent blockage of the JAK2/STAT3 and ERK signaling pathways. Furthermore, the combination of the two inhibitors resulted in a reduced tumor burden in mice. Our evidence suggests novel crosstalk between JAK2/STAT3 and ERK signaling in gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC) cells and provides a therapeutic strategy to overcome potential resistance in gastrointestinal cancer.

    Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Female; Gastrointestinal Neoplasms; Humans; Janus Kinase 2; Mice; Mice, Inbred BALB C; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Pyrrolidines; Signal Transduction; STAT3 Transcription Factor; Sulfonamides; Tumor Microenvironment

2021
Evolutionary predictability of genetic versus nongenetic resistance to anticancer drugs in melanoma.
    Cancer cell, 2021, 08-09, Volume: 39, Issue:8

    Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimal residual disease (MRD) through genetic and nongenetic mechanisms. A key question is whether specific molecular features of the MRD ecosystem determine which of these two distinct trajectories will eventually prevail. We show that, in melanoma exposed to mitogen-activated protein kinase therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD concurs with the development of nongenetic resistance. This increase relies on a glial cell line-derived neurotrophic factor-dependent signaling cascade, which activates the AKT survival pathway in a focal adhesion kinase (FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delays relapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimately escape this treatment exhibit resistance-conferring genetic alterations and increased sensitivity to extracellular signal-regulated kinase inhibition. These findings identify an approach that abrogates the nongenetic resistance trajectory in melanoma and demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths.

    Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Focal Adhesion Kinase 1; Gene Expression Regulation, Neoplastic; Glial Cell Line-Derived Neurotrophic Factor; Humans; Imidazoles; Melanoma; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Neural Crest; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2021
Trametinib overcomes KRAS-G12V-induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer.
    Cancer science, 2021, Volume: 112, Issue:9

    Leptomeningeal carcinomatosis (LMC) occurs frequently in non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third-generation EGFR-TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR-mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next-generation sequencing. We detected the Kirsten rat sarcoma (KRAS)-G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS-G12V overexpression in parental cells revealed the involvement of KRAS-G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS-G12V-harboring osimertinib-resistant LMC in EGFR-mutant NSCLC.

    Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Codon; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Mice; Mice, SCID; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Transfection; Treatment Outcome; Xenograft Model Antitumor Assays

2021
Lung Adenocarcinoma With Primary LIMD1-BRAF Fusion Treated With MEK Inhibitor: A Case Report.
    Clinical lung cancer, 2021, Volume: 22, Issue:6

    Topics: Adenocarcinoma of Lung; Aged; Humans; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Lung Neoplasms; Male; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
KRAS-driven model of Gorham-Stout disease effectively treated with trametinib.
    JCI insight, 2021, 08-09, Volume: 6, Issue:15

    Gorham-Stout disease (GSD) is a sporadically occurring lymphatic disorder. Patients with GSD develop ectopic lymphatics in bone, gradually lose bone, and can have life-threatening complications, such as chylothorax. The etiology of GSD is poorly understood, and current treatments for this disease are inadequate for most patients. To explore the pathogenesis of GSD, we performed targeted high-throughput sequencing with samples from a patient with GSD and identified an activating somatic mutation in KRAS (p.G12V). To characterize the effect of hyperactive KRAS signaling on lymphatic development, we expressed an active form of KRAS (p.G12D) in murine lymphatics (iLECKras mice). We found that iLECKras mice developed lymphatics in bone, which is a hallmark of GSD. We also found that lymphatic valve development and maintenance was altered in iLECKras mice. Because most iLECKras mice developed chylothorax and died before they had significant bone disease, we analyzed the effect of trametinib (an FDA-approved MEK1/2 inhibitor) on lymphatic valve regression in iLECKras mice. Notably, we found that trametinib suppressed this phenotype in iLECKras mice. Together, our results demonstrate that somatic activating mutations in KRAS can be associated with GSD and reveal that hyperactive KRAS signaling stimulates the formation of lymphatics in bone and impairs the development of lymphatic valves. These findings provide insight into the pathogenesis of GSD and suggest that trametinib could be an effective treatment for GSD.

    Topics: Acrylonitrile; Aniline Compounds; Animals; Bone and Bones; Disease Models, Animal; Gain of Function Mutation; High-Throughput Nucleotide Sequencing; Humans; Lymphangiogenesis; Lymphatic Vessels; Mice; Osteolysis, Essential; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Signal Transduction; Tertiary Lymphoid Structures

2021
Successful use of trametinib and dasatinib combined with chemotherapy in the treatment of Ph-positive B-cell acute lymphoblastic leukemia: A case report.
    Medicine, 2021, Jun-25, Volume: 100, Issue:25

    Relapsed or refractory acute lymphoblastic leukemia poses a significant clinical challenge due to its poor prognosis, showing survival rates of less than a year even with the use of novel therapies. In this report, we describe the safe and effective use of trametinib combined with dasatinib in a patient with acute lymphoblastic leukemia (ALL). To the best of our knowledge, this is the first report on the successful use of 2 targeted drugs such as trametinib and dasatinib in a pediatric patient with Ph+ ALL and recurrent pancreatitis.. A 6-year-old boy with ALL and Philadelphia chromosome (Ph+) who had recurrent asparaginase-associated pancreatitis.. The patient was diagnosed with ALL, based on clinical features, laboratory analyses, bone marrow aspiration evaluation in morphology, immunology, cytogenetics, and molecular.. The patient was treated with dasatinib combined with an intermediate risk-oriented chemotherapy. However, owing to recurrent asparaginase-associated pancreatitis, the patient has to abandon asparaginase in consolidation. Considering the high risk of relapse, we used trametinib and dasatinib combined with chemotherapy as maintenance chemotherapy.. After 6 months, there were no obvious side effects or residual disease.. We suggest that the combination of trametinib and dasatinib may represent a viable option to treat patients with potential relapsed/refractory Ph+ ALL.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Azathioprine; Child; Consolidation Chemotherapy; Cyclophosphamide; Cytarabine; Dasatinib; Humans; Maintenance Chemotherapy; Male; Pancreatitis; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyridones; Pyrimidinones; Treatment Outcome

2021
Fatal encephalopathy with brainstem involvement under dabrafenib and trametinib in a BRAF-positive metastatic melanoma.
    Revue neurologique, 2021, Volume: 177, Issue:9

    Topics: Brain Diseases; Brain Stem; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
Metastatic malignant melanoma mimicking a salivary gland basaloid neoplasm after treatment with nivolumab.
    Diagnostic cytopathology, 2021, Volume: 49, Issue:9

    Malignant melanoma is a well-known diagnostic pitfall, given its propensity to metastasize to different sites and mimic various entities. In this report, we present a fine-needle aspiration biopsy (FNA) of a metastatic melanoma with basaloid features that is occurring in the preauricular/parotid area. The patient is a 17-year-old male with a history of excision of melanoma of the left temple, and was undergoing adjuvant treatment with nivolumab. The prior excision was positive for S100, HMB-45, melan-A, and tyrosinase. On follow-up, he presented with non-FDG avid left preauricular area lesions. FNA was performed, and on-site evaluation demonstrated a cellular basaloid neoplasm with focal fibrillary stroma. Immunohistochemical stains revealed that the tumor cells were positive for SOX-10, S100, MITF, and HMGA2, and were negative for HMB-45, melan-A, tyrosinase, p63, cam 5.2 and PLAG1. The positive S100, SOX-10, and MITF results and negative cam 5.2 result supported the diagnosis of melanoma. Nivolumab was then stopped, Dabrafenib/Trametinib were started, and the patient underwent excision of the nodules. Nine-months later, he developed a rib metastasis that was positive for S100, SOX-10, melan-A, and tyrosinase. This report emphasizes that melanoma involving the parotid gland region has the potential to be misdiagnosed by FNA as a salivary gland neoplasm because of overlapping cytologic features and immunophenotypes. This pitfall is avoided by careful morphologic analysis and judicious use of ancillary studies.

    Topics: Adolescent; Antineoplastic Agents; Biomarkers, Tumor; Biopsy, Fine-Needle; Diagnosis, Differential; Humans; Imidazoles; Male; Melanoma; Neoplasm Metastasis; Nivolumab; Oximes; Pyridones; Pyrimidinones; Salivary Gland Neoplasms

2021
Successful use of crushed formulation of dabrafenib and trametinib in a pediatric glioneural tumor.
    Pediatric blood & cancer, 2021, Volume: 68, Issue:10

    Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Humans; Imidazoles; Mutation; Nervous System Neoplasms; Oximes; Pyridones; Pyrimidinones

2021
KRAS mutation identified in a patient with melorheostosis and extended lymphangiomatosis treated with sirolimus and trametinib.
    Clinical genetics, 2021, Volume: 100, Issue:4

    Detection of KRAS mutation in skin biopsy in a patient with melorheostosis, lymphantiomatosis and vascular stenosis. She was successfully treated with trametinib.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Child, Preschool; Disease Management; DNA-Binding Proteins; Female; Genetic Association Studies; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Lymphangioleiomyomatosis; Melorheostosis; Membrane Proteins; Mutation; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome

2021
Cost-Effectiveness Analysis of Dabrafenib Plus Trametinib and Vemurafenib as First-Line Treatment in Patients with BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma in China.
    International journal of environmental research and public health, 2021, 06-08, Volume: 18, Issue:12

    Topics: Antineoplastic Combined Chemotherapy Protocols; China; Cost-Benefit Analysis; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

2021
Monosomy 3 Is Linked to Resistance to MEK Inhibitors in Uveal Melanoma.
    International journal of molecular sciences, 2021, Jun-23, Volume: 22, Issue:13

    The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in

    Topics: Cell Line, Tumor; Chromosomes, Human, Pair 3; Diphenylamine; DNA Copy Number Variations; Drug Resistance, Neoplasm; Eukaryotic Initiation Factor-2; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Melanoma; Mitogen-Activated Protein Kinase Kinases; Monosomy; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Sulfonamides; Survival Analysis; Tumor Suppressor Proteins; Ubiquitin Thiolesterase; Uveal Neoplasms

2021
Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers.
    European journal of cancer (Oxford, England : 1990), 2021, Volume: 153

    Dabrafenib plus trametinib has demonstrated clinical benefit across multiple BRAF-mutant tumours, leading to approval for resected stage III and metastatic melanoma, non-small-cell lung cancer (NSCLC) and anaplastic thyroid cancer. Pyrexia is a common adverse event in patients treated with dabrafenib plus trametinib. Here, we characterise the incidence, patterns and management of pyrexia in patients receiving dabrafenib plus trametinib in clinical trials.. Patients (N = 1076) included in the analysis received dabrafenib plus trametinib in the following clinical trials: phase II registration trial in advanced NSCLC (N = 82), phase III COMBI-AD study in resectable stage III melanoma (N = 435) and phase III COMBI-d and COMBI-v studies in unresectable or metastatic melanoma (N = 209 and N = 350, respectively).. Among the 1076 patients enrolled in the clinical trials, 61.3% developed pyrexia, 5.7% developed grade 3/4 pyrexia and 15.6% developed a protocol-defined serious pyrexia event. Among the 660 patients with pyrexia, 33.0% had 1 occurrence, 19.8% had 2 occurrences and 47.1% had ≥3 occurrences. The incidence of pyrexia was highest early in treatment and decreased with time on treatment. Temporary dose interruption of dabrafenib or trametinib was the most common and effective management strategy.. Pyrexia is the most common adverse event associated with dabrafenib plus trametinib but is manageable with dose interruption.. ClinicalTrials.gov (Phase II NSCLC, NCT01336634; COMBI-AD, NCT01682083; COMBI-d, NCT01584648; COMBI-v, NCT01597908).

    Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Fever; Humans; Imidazoles; Male; Neoplasms; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2021
BRAF/MEK inhibitor-associated nephrotoxicity in a real-world setting and human kidney cells.
    Anti-cancer drugs, 2021, 11-01, Volume: 32, Issue:10

    Acute kidney injury (AKI) associated with cancer chemotherapy can be life-threatening. Inhibitors of rapidly accelerated fibrosarcoma kinase B (BRAF)-mutants and mitogen-activated extracellular signal-regulated kinase (MEK) administered as combination therapy are effective against BRAF-mutant melanoma, but drug-associated AKI events were reported after marketing. Here, we examined the nephrotoxicity of two BRAF inhibitors, vemurafenib and dabrafenib, and two MEK inhibitors, cobimetinib and trametinib, in a real-world setting and human kidney cells. Target drug-associated AKI signals were detected by reporting odds ratio (ROR) derived from report data in the Food and Drug Administration Adverse Events Reporting System database. In-vitro cytotoxicity was evaluated in proximal renal tubular epithelial cells (RPTEC), glomerular endothelial cells (GEnC), and glomerular epithelial cells (GEpC). AKI RORs associated with vemurafenib [ROR, 3.28; confidence interval (CI), 2.91-3.69] and cobimetinib (ROR, 4.40; CI, 3.55-5.45) were higher than those associated with dabrafenib (ROR, 1.35; CI, 1.15-1.60) and trametinib (ROR, 1.32; CI, 1.11-1.56). Vemurafenib reduced cell viability and increased cell death in RPTEC and GEpC at 10 μM, which was below the mean maximum concentration in blood under steady-state condition [115.7 μM (56.7 μg/mL)]. No vemurafenib-associated cytotoxicity was detected in GEnC. Mean maximum concentrations of cobimetinib, dabrafenib and trametinib did not induce cell death. This work revealed that vemurafenib had stronger cytotoxic effects on tubular and glomerular epithelial cells than the other BRAF and MEK inhibitors. Hence, we recommend careful monitoring for clinical signs of kidney injury in patients treated with vemurafenib.

    Topics: Acute Kidney Injury; Antineoplastic Agents; Azetidines; Cell Death; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Humans; Imidazoles; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

2021
The newly identified MEK1 tyrosine phosphorylation target MACC1 is druggable by approved MEK1 inhibitors to restrict colorectal cancer metastasis.
    Oncogene, 2021, Volume: 40, Issue:34

    Cancer metastasis causes >90% of cancer deaths and remains a major treatment challenge. Here we deciphered the impact of tyrosine phosphorylation of MACC1, a causative driver for cancer metastasis, for cancer cell signaling and novel interventions to restrict cancer metastasis. We identified MACC1 as new MEK1 substrate. MEK1 directly phosphorylates MACC1, leading to accelerated and increased ERK1 activation. Mutating in silico predicted hierarchical MACC1 tyrosine phosphorylation sites abrogates MACC1-induced migration, invasion, and MET expression, a transcriptional MACC1 target. Targeting MEK1 by RNAi or clinically applicable MEK1 inhibitors AZD6244 and GSK1120212 reduces MACC1 tyrosine phosphorylation and restricts MACC1-induced metastasis formation in mice. Although MEK1 levels, contrary to MACC1, are not of prognostic relevance for CRC patients, MEK1 expression was found indispensable for MACC1-induced metastasis. This study identifies MACC1 as new MEK1 substrate for tyrosine phosphorylation decisively impacting cell motility, tumor growth, and metastasis. Thus, MAP kinase signaling is not linear leading to ERK activation, but branches at the level of MEK1. This fundamental finding opens new therapeutic options for targeting the MEK1/MACC1 axis as novel vulnerability in patients at high risk for metastasis. This might be extended from CRC to further solid tumor entities.

    Topics: Cell Movement; Colonic Neoplasms; Humans; Mitogen-Activated Protein Kinase 3; Phosphorylation; Protein Processing, Post-Translational; Pyridones; Pyrimidinones; Signal Transduction

2021
Erlotinib and Trametinib in Patients With
    JCO precision oncology, 2021, Volume: 5

    Inhibition of the MEK/ERK pathway is critical for Bcl-2-like protein 11 (BIM)-mediated epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-induced apoptosis, and dysregulation of this pathway may be a mechanism of acquired resistance. Therefore, MEK inhibition with trametinib and an EGFR TKI may resensitize tumors with acquired resistance. Limited targeted therapies are available after progression on EGFR TKIs, and it is in this setting that we completed a phase I/II study of erlotinib and trametinib.. Patients with metastatic. Twenty-three patients were accrued; patients had received a median of two lines of prior TKI therapy (61% prior osimertinib), and 48% had acquired EGFR T790M. We confirmed one partial response (1/23, 4%, 95% CI, 0 to 22). The median progression-free survival was 1.8 months, and the median overall survival was 21 months. Diarrhea (87%), acneiform rash (87%), and fatigue (52%) were the most common treatment-related adverse events. Two patients who had tumor shrinkage both harbored a. Addition of trametinib to erlotinib in the acquired resistance setting in an unselected population is not efficacious. Future studies should focus on targeted therapies in molecularly selected populations. Acquired

    Topics: Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2021
The synergistic antitumor effect of combination therapy with a MEK inhibitor and YAP inhibitor on pERK-positive neuroblastoma.
    Biochemical and biophysical research communications, 2021, 09-17, Volume: 570

    We previously reported the in vitro and in vivo antitumor effects of trametinib, a MEK inhibitor, on neuroblastoma with MAPK pathway mutations. As we observed eventual resistance to trametinib in our previous study, we evaluated the combination therapy of CA3, a YAP inhibitor, with trametinib, based on a recent report suggesting the potential involvement of YAP in the mechanism underlying the resistance to trametinib in neuroblastoma.. SK-N-AS cells (a neuroblastoma cell line harboring RAS mutation) were treated with CA3 in vitro and subjected to a viability assay, immunocytochemistry and flow cytometry. Next, we analyzed the in vitro combination effect of CA3 and trametinib using the CompuSyn software program. Finally, we administered CA3, trametinib or both to SK-N-AS xenograft mice for 10 weeks to analyze the combination effect.. CA3 inhibited cell proliferation by both cell cycle arrest and apoptosis in vitro. Combination of CA3 and trametinib induced a significant synergistic effect in vitro (Combination Index <1). Regarding the in vivo experiment, combination therapy suppressed tumor growth, and 100% of mice in the combination therapy group survived, whereas the survival rates were 0% in the CA3 group and 33% in the trametinib group. However, despite this promising survival rate in the combination group, the tumors gradually grew after seven weeks with MAPK reactivation.. Our results indicated that CA3 and trametinib exerted synergistic antitumor effects on neuroblastoma in vitro and in vivo, and CA3 may be a viable option for concomitant drug therapy with trametinib, since it suppressed the resistance to trametinib. However, this combination effect was not sufficient to achieve complete remission. Therefore, we need to adjust the protocol to obtain a better outcome by determining the mechanism underlying regrowth in the future.

    Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Female; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Neuroblastoma; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; S Phase; Survival Analysis; Transcription Factors; Xenograft Model Antitumor Assays; YAP-Signaling Proteins

2021
Pharmacological MEK inhibition promotes polyclonal T-cell reconstitution and suppresses xenogeneic GVHD.
    Cellular immunology, 2021, Volume: 367

    Rapid immune reconstitution without developing graft-versus-host disease (GVHD) is required for the success of allogeneic hematopoietic stem cell transplantation. Here, we analyzed the effects of pharmacological MEK inhibition on human polyclonal T-cell reconstitution in a humanized mouse GVHD model utilizing deep sequencing-based T-cell receptor (TCR) repertoire analysis. GVHD mice exhibited a skewed TCR repertoire with a common clone within target organs. The MEK inhibitor trametinib ameliorated GVHD and enabled engraftment of diverse T-cell clones. Furthermore, trametinib also ameliorated GVHD sparing diverse T cell repertoire, even when it was given from day 15 through 28. Although tacrolimus also reduced development of GVHD, it disturbed diverse T cell reconstitution and resulted in skewed TCR repertoire. Thus, trametinib not only suppresses GVHD-inducing T cells but also promotes human T cell reconstitution in vivo, providing a novel rationale for translational studies targeting human GVHD.

    Topics: Animals; Cells, Cultured; Clone Cells; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Janus Kinase 3; Mice; Mice, Knockout; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptors, Antigen, T-Cell; T-Lymphocytes; Tacrolimus; Transplantation, Heterologous

2021
MEK inhibition by trametinib overcomes chemoresistance in preclinical nasopharyngeal carcinoma models.
    Anti-cancer drugs, 2021, 10-01, Volume: 32, Issue:9

    The development of chemoresistance is the major cause of treatment failure in nasopharyngeal carcinoma (NPC). Although 'paradoxical' activation of extracellular signal-regulated kinase (ERK) has been shown to contribute resistance to anticancer treatment, the role of ERK in NPC chemoresistance has not been yet revealed. In this work, we report that trametinib, a clinically available mitogen-activated protein kinase inhibitor for melanoma treatment, overcomes NPC chemoresistance via suppressing ERK activation induced by chemotherapy. We first showed that trametinib at nanomolar concentrations was active against NPC cells and acted synergistically with cisplatin. Trametinib remarkably decreased phosphorylation of ERK and its downstream effector in NPC cells. We next showed that cisplatin treatment stimulates ERK signaling, and furthermore that this can be abolished by trametinib. We finally generated cisplatin-resistant NPC models and demonstrated that trametinib was effective in inhibiting cisplatin-resistant NPC growth, colony formation and survival via suppressing ERK signaling in vitro and in vivo. Our work demonstrates the potential of trametinib in overcoming chemoresistance in preclinical NPC models and provides evidence of initializing clinical trials of using trametinib for NPC treatment.

    Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Resistance, Neoplasm; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Humans; MAP Kinase Signaling System; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Pyridones; Pyrimidinones; Signal Transduction

2021
Tumor suppressor miR-193a-3p enhances efficacy of BRAF/MEK inhibitors in BRAF-mutated colorectal cancer.
    Cancer science, 2021, Volume: 112, Issue:9

    Patients with BRAF-mutated colorectal cancer (CRC) have a poor prognosis despite recent therapeutic advances such as combination therapy with BRAF, MEK, and epidermal growth factor receptor (EGFR) inhibitors. To identify microRNAs (miRNAs) that can improve the efficacy of BRAF inhibitor dabrafenib (DAB) and MEK inhibitor trametinib (TRA), we screened 240 miRNAs in BRAF-mutated CRC cells and identified five candidate miRNAs. Overexpression of miR-193a-3p, one of the five screened miRNAs, in CRC cells inhibited cell proliferation by inducing apoptosis. Reverse-phase protein array analysis revealed that proteins with altered phosphorylation induced by miR-193a-3p were involved in several oncogenic pathways including MAPK-related pathways. Furthermore, overexpression of miR-193a-3p in BRAF-mutated cells enhanced the efficacy of DAB and TRA through inhibiting reactivation of MAPK signaling and inducing inhibition of Mcl1. Inhibition of Mcl1 by siRNA or by Mcl1 inhibitor increased the antiproliferative effect of combination therapy with DAB, TRA, and anti-EGFR antibody cetuximab. Collectively, our study demonstrated the possibility that miR-193a-3p acts as a tumor suppressor through regulating multiple proteins involved in oncogenesis and affects cellular sensitivity to MAPK-related pathway inhibitors such as BRAF inhibitors, MEK inhibitors, and/or anti-EGFR antibodies. Addition of miR-193a-3p and/or modulation of proteins involved in the miR-193a-3p-mediated pathway, such as Mcl1, to EGFR/BRAF/MEK inhibition may be a potential therapeutic strategy against BRAF-mutated CRC.

    Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cetuximab; Colorectal Neoplasms; Drug Therapy, Combination; ErbB Receptors; Genes, Tumor Suppressor; Humans; Imidazoles; MicroRNAs; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; RNA, Small Interfering; Signal Transduction; Transfection

2021
Unbiased Proteomic and Phosphoproteomic Analysis Identifies Response Signatures and Novel Susceptibilities After Combined MEK and mTOR Inhibition in BRAF
    Molecular & cellular proteomics : MCP, 2021, Volume: 20

    The mitogen-activated protein kinase pathway is one of the most frequently altered pathways in cancer. It is involved in the control of cell proliferation, invasion, and metabolism, and can cause resistance to therapy. A number of aggressive malignancies, including melanoma, colon cancer, and glioma, are driven by a constitutively activating missense mutation (V600E) in the v-Raf murine sarcoma viral oncogene homolog B (BRAF) component of the pathway. Mitogen-activated protein kinase kinase (MEK) inhibition is initially effective in targeting these cancers, but reflexive activation of mammalian target of rapamycin (mTOR) signaling contributes to frequent therapy resistance. We have previously demonstrated that combination treatment with the MEK inhibitor trametinib and the dual mammalian target of rapamycin complex 1/2 inhibitor TAK228 improves survival and decreases vascularization in a BRAF

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzoxazoles; Brain Neoplasms; Cell Line, Tumor; Female; Glioma; Humans; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Phosphoproteins; Protein Kinase Inhibitors; Proteomics; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones; TOR Serine-Threonine Kinases

2021
Trametinib enhances ATRA-induced differentiation in AML cells.
    Leukemia & lymphoma, 2021, Volume: 62, Issue:14

    All-trans retinoic acid (ATRA) is only clinically useful in acute promyelocytic leukemia (APL), but not other subtypes of acute myeloid leukemia (AML). In the present study, a clinically achievable concentration of trametinib, a highly selective inhibitor of MEK, enhanced ATRA-induced differentiation in AML cell lines, HL-60 and U937 as well as AML primary cells. Moreover, trametinib-ATRA (tra-ATRA) co-treatment restored ATRA sensitivity in ATRA-resistant AML cell line, HL-60Res. The protein level of STAT3 and the phosphorylation of Akt or JNK were enhanced with tra-ATRA treatment in HL-60, U937, and HL-60Res cells, respectively. Furthermore, tra-ATRA-induced differentiation in HL-60, U937, and HL-60Res cells was inhibited by STAT3, PI3K, and JNK inhibitors, respectively. Therefore, STAT3, Akt, and JNK signaling pathways were involved in tra-ATRA-induced differentiation in HL-60, U937, and HL-60Res cells, respectively. Taken together, our findings may provide novel therapeutic strategies for AML patients.

    Topics: Cell Differentiation; HL-60 Cells; Humans; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Tretinoin

2021
Inhibition of MEK pathway enhances the antitumor efficacy of chimeric antigen receptor T cells against neuroblastoma.
    Cancer science, 2021, Volume: 112, Issue:10

    Disialoganglioside (GD2)-specific chimeric antigen receptor (CAR)-T cells (GD2-CAR-T cells) have been developed and tested in early clinical trials in patients with relapsed/refractory neuroblastoma. However, the effectiveness of immunotherapy using these cells is limited, and requires improvement. Combined therapy with CAR-T cells and molecular targeted drugs could be a promising strategy to enhance the antitumor efficacy of CAR T cell immunotherapy. Here, we generated GD2-CAR-T cells through piggyBac transposon (PB)-based gene transfer (PB-GD2-CAR-T cells), and analyzed the combined effect of these cells and a MEK inhibitor in vitro and in vivo on neuroblastoma. Trametinib, a MEK inhibitor, ameliorated the killing efficacy of PB-GD2-CAR-T cells in vitro, whereas a combined treatment of the two showed superior antitumor efficacy in a murine xenograft model compared to that of PB-GD2-CAR-T cell monotherapy, regardless of the mutation status of the MAPK pathway in tumor cells. The results presented here provide new insights into the feasibility of combined treatment with CAR-T cells and MEK inhibitors in patients with neuroblastoma.

    Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Combined Modality Therapy; Coumarins; DNA Transposable Elements; Drug Resistance, Neoplasm; Female; Gangliosides; Genetic Therapy; Humans; Immunotherapy, Adoptive; Mice; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasm Recurrence, Local; Neuroblastoma; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; ras Proteins; Receptors, Chimeric Antigen; T-Lymphocytes; Xenograft Model Antitumor Assays

2021
MEK inhibition overcomes resistance to EphA2-targeted therapy in uterine cancer.
    Gynecologic oncology, 2021, Volume: 163, Issue:1

    Our pilot clinical study of EphA2 inhibitor (dasatinib) plus paclitaxel and carboplatin showed interesting clinical activity in endometrial cancer with manageable toxicity. However, the underlying mechanisms of dasatinib resistance in uterine cancer are unknown. Here, we investigated potential mechanisms underlying resistance to EphA2 inhibitors in uterine cancer and examined the anti-tumor activity of EphA2 inhibitors alone and in combination with a MEK inhibitor.. We evaluated the antitumor activity of EphA2 inhibitors plus a MEK inhibitor using in vitro and in vivo orthotopic models of uterine cancer.. EphA2 inhibitor induced MAPK in dasatinib-resistant uterine cancer cells (HEC-1A and Ishikawa) and BRAF/CRAF heterodimerization in HEC-1A cells. EphA2 inhibitor and trametinib significantly increased apoptosis in cancer cells resistant to EphA2 inhibitors compared with controls (p < 0.01). An in vivo study with the orthotopic HEC-1A model showed significantly greater antitumor response to combination treatment compared with dasatinib alone (p < 0.01). Combination treatment increased EphrinA1 and BIM along with decreased pMAPK, Jagged 1, and c-MYC expression in dasatinib-resistant cells. In addition, Spearman analysis using the TCGA data revealed that upregulation of EphA2 was significantly correlated with JAG1, MYC, NOTCH1, NOTCH3 and HES1 expression (p < 0.001, r = 0.25-0.43). Specifically, MAP3K15 and the NOTCH family genes were significantly related to poor clinical outcome in patients with uterine cancer.. These findings indicate that the MAPK pathway is activated in dasatinib-resistant uterine cancer cells and that EphrinA1-mediated MEK inhibition overcomes dasatinib resistance. Dual targeting of both EphA2 and MEK, combined with chemotherapy, should be considered for future clinical development.

    Topics: Animals; Apoptosis; Cell Line, Tumor; Dasatinib; Drug Resistance, Neoplasm; Female; Humans; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Pyridones; Pyrimidinones; Receptor, EphA2; Uterine Neoplasms

2021
A novel treatment strategy for lapatinib resistance in a subset of HER2-amplified gastric cancer.
    BMC cancer, 2021, Aug-16, Volume: 21, Issue:1

    Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Human epidermal growth factor receptor 2 (HER2) amplification occurs in approximately 13-23% of all GC cases and patients with HER2 overexpression exhibit a poor prognosis. Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, is an effective agent to treat HER2-amplified breast cancer but it failed in gastric cancer (GC) clinical trials. However, the molecular mechanism of lapatinib resistance in HER2-amplified GC is not well studied.. We employed an unbiased, genome-scale screening with pooled CRISPR library on HER2-amplified GC cell lines to identify genes that are associated with resistance to lapatinib. To validate the candidate genes, we applied in vitro and in vivo pharmacological tests to confirm the function of the target genes.. We found that loss of function of CSK or PTEN conferred lapatinib resistance in HER2-amplified GC cell lines NCI-N87 and OE19, respectively. Moreover, PI3K and MAPK signaling was significantly increased in CSK or PTEN null cells. Furthermore, in vitro and in vivo pharmacological study has shown that lapatinib resistance by the loss of function of CSK or PTEN, could be overcome by lapatinib combined with the PI3K inhibitor copanlisib and MEK inhibitor trametinib.. Our study suggests that loss-of-function mutations of CSK and PTEN cause lapatinib resistance by re-activating MAPK and PI3K pathways, and further proved these two pathways are druggable targets. Inhibiting the two pathways synergistically are effective to overcome lapatinib resistance in HER2-amplified GC. This study provides insights for understanding the resistant mechanism of HER2 targeted therapy and novel strategies that may ultimately overcome resistance or limited efficacy of lapatinib treatment for subset of HER2 amplified GC.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Lapatinib; Mice; Mice, Inbred NOD; Mice, SCID; Pyridones; Pyrimidines; Pyrimidinones; Quinazolines; Receptor, ErbB-2; Stomach Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2021
Rapamycin and trametinib: a rational combination for treatment of NSCLC.
    International journal of biological sciences, 2021, Volume: 17, Issue:12

    Mammalian target of rapamycin (mTOR) is one of the most commonly activated pathways in human cancers, including lung cancer. Targeting mTOR with molecule inhibitors is considered as a useful therapeutic strategy. However, the results obtained from the clinical trials with the inhibitors so far have not met the original expectations, largely because of the drug resistance. Thus, combined or multiple drug therapy can bring about more favorable clinical outcomes. Here, we found that activation of ERK pathway was responsible for rapamycin drug resistance in non-small-cell lung cancer (NSCLC) cells. Accordingly, rapamycin-resistant NSCLC cells were more sensitive to ERK inhibitor (ERKi), trametinib, and in turn, trametinib-resistant NSCLC cells were also susceptible to rapamycin. Combining rapamycin with trametinib led to a potent synergistic antitumor efficacy, which induced G1-phase cycle arrest and apoptosis. In addition, rapamycin synergized with another ERKi, MEK162, and in turn, trametinib synergized with other mTORi, Torin1 and OSI-027. Mechanistically, rapamycin in combination with trametinib resulted in a greater decrease of phosphorylation of AKT, ERK, mTOR and 4EBP1. In xenograft mouse model, co-administration of rapamycin and trametinib caused a substantial suppression in tumor growth without obvious drug toxicity. Overall, our study identifies a reasonable combined strategy for treatment of NSCLC.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Immunohistochemistry; Lung Neoplasms; Mice, Inbred BALB C; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Sirolimus; Xenograft Model Antitumor Assays

2021
Response to trametinib of histiocytosis with an activating
    Leukemia & lymphoma, 2020, Volume: 61, Issue:1

    Topics: Histiocytosis; Humans; Mutation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyridones; Pyrimidinones

2020
Pharmacological inhibition of the MEK5/ERK5 and PI3K/Akt signaling pathways synergistically reduces viability in triple-negative breast cancer.
    Journal of cellular biochemistry, 2020, Volume: 121, Issue:2

    Triple-negative breast cancers (TNBCs) represent 15% to 20% of all breast cancers and are often associated with poor prognosis. The lack of targeted therapies for TNBCs contributes to higher mortality rates. Aberrations in the phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. While the crosstalk between PI3K and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways has been characterized in several systems, new evidence suggests that MEK5/ERK5 signaling is a key component in the proliferation and survival of several aggressive cancers. In this study, we examined the effects of dual inhibition of PI3K/protein kinase B (Akt) and MEK5/ERK5 in the MDA-MB-231, BT-549, and MDA-MB-468 TNBC cell lines. We used the Akt inhibitor ipatasertib, ERK5 inhibitors XMD8-92 and AX15836, and the novel MEK5 inhibitor SC-1-181 to investigate the effects of dual inhibition. Our results indicated that dual inhibition of PI3K/Akt and MEK5/ERK5 signaling was more effective at reducing the proliferation and survival of TNBCs than single inhibition of either pathway alone. In particular, a loss of Bad phosphorylation at two distinct sites was observed with dual inhibition. Furthermore, the inhibition of both pathways led to p21 restoration, decreased cell proliferation, and induced apoptosis. In addition, the dual inhibition strategy was determined to be synergistic in MDA-MB-231 and BT-549 cells and was relatively nontoxic in the nonneoplastic MCF-10 cell line. In summary, the results from this study provide a unique prospective into the utility of a novel dual inhibition strategy for targeting TNBCs.

    Topics: Apoptosis; Benzodiazepinones; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Drug Synergism; Female; Humans; MAP Kinase Kinase 5; Mitogen-Activated Protein Kinase 7; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperazines; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidines; Pyrimidinones; Signal Transduction; Triple Negative Breast Neoplasms

2020
MEK/MELK inhibition and blood-brain barrier deficiencies in atypical teratoid/rhabdoid tumors.
    Neuro-oncology, 2020, 01-11, Volume: 22, Issue:1

    Atypical teratoid/rhabdoid tumors (AT/RT) are rare, but highly aggressive. These entities are of embryonal origin occurring in the central nervous system (CNS) of young children. Molecularly these tumors are driven by a single hallmark mutation, resulting in inactivation of SMARCB1 or SMARCA4. Additionally, activation of the MAPK signaling axis and preclinical antitumor efficacy of its inhibition have been described in AT/RT.. We established and validated a patient-derived neurosphere culture and xenograft model of sonic hedgehog (SHH) subtype AT/RT, at diagnosis and relapse from the same patient. We set out to study the vascular phenotype of these tumors to evaluate the integrity of the blood-brain barrier (BBB) in AT/RT. We also used the model to study combined mitogen-activated protein kinase kinase (MEK) and maternal embryonic leucine zipper kinase (MELK) inhibition as a therapeutic strategy for AT/RT.. We found MELK to be highly overexpressed in both patient samples of AT/RT and our primary cultures and xenografts. We identified a potent antitumor efficacy of the MELK inhibitor OTSSP167, as well as strong synergy with the MEK inhibitor trametinib, against primary AT/RT neurospheres. Additionally, vascular phenotyping of AT/RT patient material and xenografts revealed significant BBB aberrancies in these tumors. Finally, we show in vivo efficacy of the non-BBB penetrable drugs OTSSP167 and trametinib in AT/RT xenografts, demonstrating the therapeutic implications of the observed BBB deficiencies and validating MEK/MELK inhibition as a potential treatment.. Altogether, we developed a combination treatment strategy for AT/RT based on MEK/MELK inhibition and identify therapeutically exploitable BBB deficiencies in these tumors.

    Topics: Animals; Blood-Brain Barrier; Cell Proliferation; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Naphthyridines; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyridones; Pyrimidinones; Rhabdoid Tumor; Spheroids, Cellular; Teratoma; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2020
Simultaneous targeted therapy for metastatic melanoma and hepatitis C.
    Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 2020, Volume: 18, Issue:1

    Topics: Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Benzimidazoles; Fluorenes; Hepatitis C, Chronic; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Sofosbuvir; Uridine Monophosphate

2020
A genome-wide CRISPR screen identifies FBXO42 involvement in resistance toward MEK inhibition in NRAS-mutant melanoma.
    Pigment cell & melanoma research, 2020, Volume: 33, Issue:2

    NRAS mutations are the most common alterations among RAS isoforms in cutaneous melanoma, with patients harboring these aggressive tumors having a poor prognosis and low survival rate. The main line of treatment for these patients is MAPK pathway-targeted therapies, such as MEK inhibitors, but, unfortunately, the response to these inhibitors is variable due to tumor resistance. Identifying genetic modifiers involved in resistance toward MEK-targeted therapy may assist in the development of new therapeutic strategies, enhancing treatment response and patient survival. Our whole-genome CRISPR-Cas9 knockout screen identified the target Kelch domain-containing F-Box protein 42 (FBXO42) as a factor involved in NRAS-mutant melanoma-acquired resistance to the MEK1/2 inhibitor trametinib. We further show that FBXO42, an E3 ubiquitin ligase, is involved in the TAK1 signaling pathway, possibly prompting an increase in active P38. In addition, we demonstrate that combining trametinib with the TAK1 inhibitor, takinib, is a far more efficient treatment than trametinib alone in NRAS-mutant melanoma cells. Our findings thus show a new pathway involved in NRAS-mutant melanoma resistance and provide new opportunities for novel therapeutic options.

    Topics: Base Sequence; Biomarkers, Tumor; Cell Line, Tumor; CRISPR-Cas Systems; Drug Resistance, Neoplasm; F-Box Proteins; Genetic Testing; Genome, Human; GTP Phosphohydrolases; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Melanoma; Membrane Proteins; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Mutation; Protein Binding; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

2020
Dipyridamole Enhances the Cytotoxicities of Trametinib against Colon Cancer Cells through Combined Targeting of HMGCS1 and MEK Pathway.
    Molecular cancer therapeutics, 2020, Volume: 19, Issue:1

    Both the MAPK pathway and mevalonate (MVA) signaling pathway play an increasingly significant role in the carcinogenesis of colorectal carcinoma, whereas the cross-talk between these two pathways and its implication in targeted therapy remains unclear in colorectal carcinoma. Here, we identified that HMGCS1 (3-hydroxy-3-methylglutaryl-CoA synthase 1), the rate-limiting enzyme of the MVA pathway, is overexpressed in colon cancer tissues and positively regulates the cell proliferation, migration, and invasion of colon cancer cells. In addition, HMGCS1 could enhance the activity of pERK independent of the MVA pathway, and the suppression of HMGCS1 could completely reduce the EGF-induced proliferation of colon cancer cells. Furthermore, we found that trametinib, a MEK inhibitor, could only partially abolish the upregulation of HMGCS1 induced by EGF treatment, while combination with HMGCS1 knockdown could completely reverse the upregulation of HMGCS1 induced by EGF treatment and increase the sensitivity of colon cancer cells to trametinib. Finally, we combined trametinib and dipyridamole, a common clinically used drug that could suppress the activity of SREBF2 (sterol regulatory element-binding transcription factor 2), a transcription factor regulating HMGCS1 expression, and identified its synergistic effect in inhibiting the proliferation and survival of colon cancer cells

    Topics: Animals; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Dipyridamole; Female; Humans; Hydroxymethylglutaryl-CoA Synthase; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Mice, SCID; Pyridones; Pyrimidinones; Transfection

2020
Dual inhibition of BRAF and MEK increases expression of sodium iodide symporter in patient-derived papillary thyroid cancer cells in vitro.
    Surgery, 2020, Volume: 167, Issue:1

    The majority of papillary thyroid cancers are driven by acquired mutations typically in the BRAF or RAS genes that aberrantly activate the mitogen-activated protein kinase pathway. This process leads to malignant transformation, dedifferentiation, and a decrease in the expression of the sodium-iodide symporter (NIS; SLC5A5), which results in resistance to radioactive iodine therapy. We sought to determine whether inhibition of aberrant mitogen-activated protein kinase-signaling can restore NIS expression.. We prospectively developed cultures of papillary thyroid cancers derived from operative specimens and applied drug treatments for 24 hours. Samples were genotyped to identify BRAF and RAS mutations. We performed quantitative PCR to measure NIS expression after treatment.. We evaluated 24 patient papillary thyroid cancer specimens; BRAF. Dual treatment with BRAF and MEK inhibitors upregulated NIS expression, suggesting that this treatment regimen may increase tumor iodine uptake. The effect was greatest in tumor cells from younger patients.

    Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Female; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Iodine Radioisotopes; Male; MAP Kinase Signaling System; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Primary Cell Culture; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Radiation Tolerance; Symporters; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tumor Cells, Cultured; Up-Regulation

2020
Potassium iodide in successful treatment of erythema nodosum-like lesions induced by combination therapy with dabrafenib and trametinib.
    The Journal of dermatology, 2020, Volume: 47, Issue:1

    Topics: Antineoplastic Agents; Dermatologic Agents; Erythema Nodosum; Female; Humans; Imidazoles; Melanoma; Middle Aged; Mutation; Oximes; Potassium Iodide; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2020
TYRP1 mRNA level is stable and MITF-M-independent in drug-naïve, vemurafenib- and trametinib-resistant BRAF
    Archives of dermatological research, 2020, Volume: 312, Issue:5

    TYRP1 mRNA is of interest due to its potential non-coding role as a sponge sequestering tumor-suppressive miRs in melanoma. To our knowledge, there is no report on changes in TYRP1 expression in melanomas after development of resistance to targeted therapies. We used patient-derived drug-naïve RAS

    Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Membrane Glycoproteins; Microphthalmia-Associated Transcription Factor; Mutation; Neoplasm Recurrence, Local; Oxidoreductases; Protein Isoforms; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; RNA, Messenger; Skin Neoplasms; Vemurafenib

2020
Response to the combination of dabrafenib, trametinib and osimertinib in a patient with EGFR-mutant NSCLC harboring an acquired BRAF
    Lung cancer (Amsterdam, Netherlands), 2020, Volume: 139

    Topics: Acrylamides; Aniline Compounds; ErbB Receptors; Humans; Imidazoles; Liquid Biopsy; Lung Neoplasms; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2020
Pneumocephalus in a Pediatric Patient with Glioma Receiving Trametinib.
    Pediatric neurosurgery, 2020, Volume: 55, Issue:1

    The mitogen-activated protein kinase (MAPK) pathway consists of the Ras/Raf/MEK/ERK signaling cascade, and its upregulation plays a major role in the pathogenesis of pediatric astrocytomas and molecular inhibitors of this pathway including trametinib and dabrafenib have been tested in early-phase clinical trials and used by pediatric oncologists in children with BRAF-mutated gliomas. We report a clinical case where a child with progressive BRAF-mutated glioma developed an uncommon and difficult to manage complication - pneumocephalus from intracranial air entry and trapping through dehisced surgical wounds and preexisting skull burr holes. The patient's wound breakdown coincided with skin toxicity from MEK inhibitor therapy. With increasing use of targeted molecular inhibitors in pediatric neuro-oncology, this case illustrates the potentially complicated course of MEK inhibitor therapy in patients with scalp surgical wounds and burr holes that were placed within few weeks from initiation of drug therapy, especially if patients have additional factors that can contribute to poor wound healing such as use of steroids and malnutrition.

    Topics: Child, Preschool; Female; Glioma; Humans; MAP Kinase Signaling System; Pneumocephalus; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Surgical Wound Dehiscence

2020
Recalcitrant trametinib-induced paronychia treated successfully with topical timolol in a pediatric patient.
    Dermatologic therapy, 2020, Volume: 33, Issue:1

    Paronychia has been described as a side effect in patients undergoing treatment with MEK (mitogen activated protein kinase enzyme) inhibitors. It is usually a recurrent condition that can have a significant impact in the quality of life. Topical beta blocker treatment has been described as an effective therapy in antineoplastic-induced pyogenic granulomas and in antineoplastic-induced paronychia. We describe the first case treated with topical timolol for a trametinib-induced paronychia in a pediatric patient that allowed to continue the third line antineoplastic therapy for his glioma.

    Topics: Administration, Topical; Adrenergic beta-Antagonists; Antineoplastic Agents; Child, Preschool; Glioma; Humans; Male; Paronychia; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Timolol; Treatment Outcome

2020
Using personalized medicine in gliomas: a genomic approach to diagnosis and overcoming treatment resistance in a case with pleomorphic xanthoastrocytoma.
    Journal of neurology, 2020, Volume: 267, Issue:3

    A patient who was initially considered to have a glioblastoma (GBM) had molecular analysis, showing that it was a pleomorphic xanthoastrocytoma (PXA). Up to 78% of PXA tumors have BRAF V600E mutations. Primary brain tumors with BRAF mutations can have a good response to BRAF MEK inhibitors (BRAF MEKi), and there may be a synergistic response when combined with autophagy inhibitors.. A 20-year-old man found to have a large brain mass with midline shift underwent resection. He was diagnosed with "GBM" and treated with radiation and temozolomide with subsequent disease recurrence. Review of histology showed malignant PXA with BRAF V600E mutation. Treatment with Dabrafenib and Trametinib was started, and tumor size increased in size after 14 months of treatment. Given studies showing that resistance to BRAF inhibition can be overcome by autophagy inhibition, chloroquine was added. Patient has been on "triple" therapy for 15 months and has radiographically Stable Disease. At MCC, 3% of patients with gliomas have BRAF mutations who could potentially benefit from this combination therapy.. This is the first report of a PXA patient receiving therapy with BRAF MEKi and an autophagy inhibitor with prolonged stable disease. This patient highlights the importance of a molecular interrogation in gliomas to provide an integrated diagnosis and effective treatment. This may be useful in up to 3% of glioma patients with BRAF mutations. Molecular testing in neuro-oncology is providing new avenues of diagnosis and treatment, and detailed molecular interrogation should be considered routine.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Brain Neoplasms; Chloroquine; Drug Resistance, Neoplasm; Humans; Imidazoles; Male; Oximes; Precision Medicine; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

2020
Decitabine limits escape from MEK inhibition in uveal melanoma.
    Pigment cell & melanoma research, 2020, Volume: 33, Issue:3

    MEK inhibitors (MEKi) demonstrate anti-proliferative activity in patients with metastatic uveal melanoma, but responses are short-lived. In the present study, we evaluated the MEKi trametinib alone and in combination with drugs targeting epigenetic regulators, including DOT1L, EZH2, LSD1, DNA methyltransferases, and histone acetyltransferases. The DNA methyltransferase inhibitor (DNMTi) decitabine effectively enhanced the anti-proliferative activity of trametinib in cell viability, colony formation, and 3D organoid assays. RNA-Seq analysis showed the MEKi-DNMTi combination primarily affected the expression of genes involved in G1 and G2/2M checkpoints, cell survival, chromosome segregation and mitotic spindle. The DNMTi-MEKi combination did not appear to induce a DNA damage response (as measured by γH2AX foci) or senescence (as measured by β-galactosidase staining) compared to either MEKi or DNMTi alone. Instead, the combination increased expression of the CDK inhibitor p21 and the pro-apoptotic protein BIM. In vivo, the DNMTi-MEKi combination was more effective at suppressing growth of MP41 uveal melanoma xenografts than either drug alone. Our studies indicate that DNMTi may enhance the activity of MEKi in uveal melanoma.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Decitabine; Female; Humans; Melanoma; Mice; Mitogen-Activated Protein Kinase Kinases; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Uveal Neoplasms; Xenograft Model Antitumor Assays

2020
[Stage III melanoma: Sentinel node biopsy, completion lymph node dissection and prospects of adjuvant therapy. A French national survey on current and envisaged practices].
    Annales de dermatologie et de venereologie, 2020, Volume: 147, Issue:1

    The recent publication of randomized trials investigating the efficacy of adjuvant therapy and completion lymph node dissection at microscopic stage III melanoma calls for a reappraisal of melanoma management from different angles: indications for sentinel lymph node biopsy, indications for completion lymph node dissection in microscopic-stage disease, and adjuvant therapies. Our objective was to evaluate current practices and to question French onco-dermatologists about any changes they envisaged in their practices in the light of recent publications.. We conducted a national survey among members of the Cutaneous Oncology Group of the French Society of Dermatology in October 2017.. Forty French health centers were included, and 53 individual responses were collected. Sentinel lymph node biopsy for melanoma was performed at 75 % of the centers. Before the summer of 2017 and the publication of MSLT-II (proving the absence of any therapeutic benefits for complete lymph node dissection in microscopic stage III melanoma), when a positive sentinel lymph node was diagnosed, immediate completion lymph node dissection was performed at 90 % of the centers. After the publication of MSLT-II, 45 % of the respondents considered stopping this practice. The risk-benefit ratio prompted prescription of nivolumab and of combined dabrafenib+trametinib as adjuvant therapy by respectively 96 % and 79 % of respondents, while the corresponding rates for interferon and ipilimumab were only 21 % and 15 %.. Early melanoma management stands on the verge of major changes thanks to the arrival of efficient adjuvant therapies and a decrease in immediate completion lymph node dissections for patients with microscopic stage III is also anticipated.

    Topics: Antineoplastic Agents; Chemotherapy, Adjuvant; France; Health Care Surveys; Humans; Imidazoles; Interferons; Ipilimumab; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Oximes; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Risk Assessment; Sentinel Lymph Node; Sentinel Lymph Node Biopsy; Skin Neoplasms

2020
Remarkable elevation of fibrinolysis markers and procalcitonin associated with dabrafenib plus trametinib combination therapy: Uncommon adverse events.
    The Journal of dermatology, 2020, Volume: 47, Issue:2

    Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Fibrinolysis; Humans; Imidazoles; Lung; Lung Neoplasms; Male; Melanoma; Mutation; Oximes; Procalcitonin; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Young Adult

2020
Surgical approach to patients with low-burden stage III melanoma: Is it time to consider conservative surgery?
    European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology, 2020, Volume: 46, Issue:4 Pt A

    Topics: Chemotherapy, Adjuvant; Disease-Free Survival; Humans; Imidazoles; Lymph Node Excision; Melanoma; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sentinel Lymph Node; Sentinel Lymph Node Biopsy; Skin Neoplasms; Survival Rate; Tumor Burden

2020
Posterior reversible encephalopathy syndrome in a melanoma patient with dabrafenib and trametinib treatment following immunotherapy.
    Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG, 2020, Volume: 18, Issue:2

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Immunotherapy; Ipilimumab; Melanoma; Nivolumab; Oximes; Posterior Leukoencephalopathy Syndrome; Pyridones; Pyrimidinones; Skin Neoplasms

2020
ERK inhibition effectively overcomes acquired resistance of epidermal growth factor receptor-mutant non-small cell lung cancer cells to osimertinib.
    Cancer, 2020, 03-15, Volume: 126, Issue:6

    Osimertinib (AZD9291), a third-generation, mutation-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI), is an approved drug for patients who have non-small cell lung cancer (NSCLC) with activating EGFR mutations or those harboring a resistant T790M mutation. Unfortunately, all patients eventually relapse and develop resistance to osimertinib. The current study addressed whether ERK inhibition exerts effects similar to those produced by MEK inhibition in overcoming acquired resistance to osimertinib.. Drug effects on cell and tumor growth were assessed by measuring cell number alterations and colony formation in vitro and with xenografts in nude mice in vivo. Apoptosis was assessed with annexin V/flow cytometry and protein cleavage. Protein alterations in cells were detected with Western blot analysis. Gene overexpression and knockout were achieved with lentiviral infection and CRISPR/Cas9, respectively.. The combination of osimertinib with an ERK inhibitor synergistically decreased the survival of osimertinib-resistant cell lines with enhanced induction of apoptosis and effectively inhibited the growth of osimertinib-resistant xenografts in nude mice. Moreover, the combination of an MEK or ERK inhibitor with a first-generation (eg, erlotinib) or second-generation (eg, afatinib) EGFR-TKI also very effectively inhibited the growth of osimertinib-resistant cells in vitro and of tumors in vivo, although these cell lines were cross-resistant to first-generation or second-generation EGFR-TKIs.. The current findings emphasize the importance of targeting MEK/ERK signaling in maintaining the long-term benefit of osimertinib through overcoming acquired resistance to osimertinib, warranting further investigation of this therapeutic strategy to improve the therapeutic efficacy of osimertinib in the clinic.

    Topics: Acrylamides; Afatinib; Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Therapy, Combination; ErbB Receptors; Erlotinib Hydrochloride; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mice; Mice, Nude; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Neoplastic Stem Cells; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2020
Successful treatment of occult pancreatic melanoma using BRAF/MEK inhibitors.
    The Journal of dermatology, 2020, Volume: 47, Issue:4

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Asymptomatic Diseases; Biopsy, Fine-Needle; Female; Humans; Imidazoles; Liver Neoplasms; Melanoma; Mitogen-Activated Protein Kinase Kinases; Oximes; Pancreas; Pancreatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography

2020
Real-world efficacy and safety data for dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced melanoma.
    The Journal of dermatology, 2020, Volume: 47, Issue:3

    We conducted a retrospective investigation of the efficacy and safety of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced melanoma in real-world clinical practise. The study analyzed 50 patients who received dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive advanced melanoma in our hospital (26 men and 24 women, aged 21-86 years, inclusive; median age, 53 years). The response rate was 72.3%, with complete response (CR) achieved in eight cases (17.0%), partial response in 26 (55.3%), stable disease in nine (19.1%) and progressive disease in four (8.5%). Median progression-free survival (PFS) was 12 months, and median overall survival (OS) was 23 months. Disease progression occurred in 29 of the 50 patients during the study period, and 25 patients died. Baseline lactate dehydrogenase and the number of organs with metastasis were important predictive factors for PFS and OS, and CR to combination therapy was a predictive factor for long-term remission. Adverse events occurred in 88% of cases; 16% were grade 3 or worse. The adverse events observed in 50% of more of patients were rash (56%) and pyrexia (52%). The efficacy of dabrafenib and trametinib combination therapy in Japanese patients was similar to that reported in global studies, and the same adverse events were generally reported; however, rash tended to occur more frequently in the patients in our study.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Eruptions; Exanthema; Female; Fever; Humans; Imidazoles; Japan; L-Lactate Dehydrogenase; Male; Melanoma; Middle Aged; Mutation; Oximes; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Skin Neoplasms; Survival Rate; Young Adult

2020
Myasthenia gravis following dabrafenib and trametinib for metastatic melanoma.
    Neurology, 2020, 02-18, Volume: 94, Issue:7

    Topics: Aged; Antineoplastic Agents; Humans; Imidazoles; Male; Melanoma; Myasthenia Gravis; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Scalp; Skin Neoplasms

2020
Dabrafenib plus trametinib is effective in the treatment of BRAF V600-mutated metastatic melanoma patients: analysis of patients from the dabrafenib plus trametinib Named Patient Program (DESCRIBE II).
    Melanoma research, 2020, Volume: 30, Issue:3

    In clinical trials, dabrafenib plus trametinib improved overall survival (OS) compared with single-agent BRAF inhibitors (BRAFi) in patients with BRAF V600-mutant unresectable or metastatic melanoma. We investigated dabrafenib plus trametinib therapy in a compassionate-use setting [Named Patient Program (NPP); DESCRIBE II]. A retrospective chart review of patients with BRAF V600-mutated unresectable stage III/IV melanoma receiving dabrafenib plus trametinib as compassionate use was conducted. Treatment patterns and duration, clinical outcomes, and tolerability were evaluated. Of 271 patients, 92.6% had stage IV melanoma, including 36.5% with brain metastases. Overall, 162 patients (59.8%) were BRAFi naive and 171 (63.1%) received first-line dabrafenib plus trametinib. Among BRAFi-naive patients, the overall response rate (ORR) was 67.3%, median OS (mOS) was 20.0 months, and median progression-free survival (mPFS) was 7.5 months. In BRAFi-naive patients with known brain metastases (n = 62), ORR was 61.3%, mOS was 15.5 months, and mPFS was 6.2 months. Eighty-four patients received BRAFi monotherapy for >30 days and switched to dabrafenib plus trametinib prior to progression. Of these 84 patients, 63 had known disease status at the time of switch, and 22 improved with the combination therapy. No new safety signals were identified, and dabrafenib plus trametinib was well tolerated. Dabrafenib plus trametinib showed substantial clinical activity in NPP patients with BRAF V600-mutated unresectable or metastatic melanoma. Analysis of treatment patterns demonstrated the effectiveness of the combination in patients with brain metastases and across lines of therapy with a well tolerated and manageable safety profile.

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Compassionate Use Trials; Disease-Free Survival; Female; Humans; Imidazoles; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome

2020
Trametinib alleviates lipopolysaccharide-induced acute lung injury by inhibiting the MEK-ERK-Egr-1 pathway.
    International immunopharmacology, 2020, Volume: 80

    Acute lung injury (ALI) is a devastating clinical disorder with a high mortality rate and for which there is no effective treatment. The main characteristic of ALI is uncontrolled inflammation, and macrophages play a critical role in the development of this disorder. Trametinib, an inhibitor of MAPK/ERK kinase (MEK) activity that possesses anti-inflammatory properties, has been approved for clinical use. Herein, the influence of trametinib and its underlying mechanism were investigated using a lipopolysaccharide (LPS)-induced murine ALI model. We found that trametinib treatment prevented the LPS-facilitated expression of proinflammatory mediators in macrophages, and this anti-inflammatory action was closely correlated with suppression of the MEK-ERK-early growth response (Egr)-1 pathway. Furthermore, trametinib treatment alleviated LPS-induced ALI in mice, and attenuated edema, proinflammatory mediator production, and neutrophil infiltration. Trametinib pretreatment also attenuated the MEK-ERK-Egr-1 pathway in lung tissues. In conclusion, these data demonstrate that trametinib pretreatment suppresses inflammation in LPS-activated macrophages in vitro and protects against murine ALI established by LPS administration in vivo through inhibition of the MEK-ERK-Egr-1 pathway. Therefore, trametinib might have therapeutic potential for ALI.

    Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Cells, Cultured; Cytokines; Early Growth Response Protein 1; Extracellular Signal-Regulated MAP Kinases; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Pyridones; Pyrimidinones; RAW 264.7 Cells; Signal Transduction

2020
Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity.
    Cells, 2020, 01-07, Volume: 9, Issue:1

    Topics: Adaptation, Physiological; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Neoplasm Proteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Receptors, Nerve Growth Factor; RNA, Messenger; Signal Transduction; Vemurafenib

2020
Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors.
    Cancer medicine, 2020, Volume: 9, Issue:5

    Molecular-targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK-PI3K drug therapy against KRAS mutated mucin 2 (MUC2)-secreting LS174T cells and patient-derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity to this targeted co-therapy. Co-treatment with MEK inhibitor (trametinib) and PI3K inhibitor (pictilisib)-induced synergistic cytotoxicity and intrinsic mitochondrial-mediated apoptosis in LS174T cells and tumor explants in vitro. Dual drug therapy also induced endoplasmic reticulum stress (ERS)-associated proteins (GRP78/BiP, ATF4, and CHOP). However, CHOP knock-down assays demonstrated that mitochondrial-mediated apoptosis in LS174T cells was not ERS-dependent. Dual drug therapy also significantly decreased MUC2 expression, MUC2 post-translational modification (palmitoylation) and secretion in LS174T cells, suggesting a simultaneous cytotoxic and mucin suppressive mechanism of action. We also demonstrated effective mucinous tumor growth suppression in ex vivo epithelial organoid (colonoid) cultures and in in vivo intraperitoneal patient-derived xenograft models derived from mucinous colon/appendix cancer. These promising preclinical data support a role for dual MEK-PI3K inhibitor therapy in mucinous colon/appendix cancers. We postulate that mucinous KRAS mutated cancers are especially vulnerable to this co-treatment based on their unique phenotypic and genotypic characteristics.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Appendiceal Neoplasms; Appendix; Cell Line, Tumor; Chemotherapy, Adjuvant; Colon; Colonic Neoplasms; Drug Synergism; Endoplasmic Reticulum Chaperone BiP; Female; Humans; Indazoles; Intestinal Mucosa; Mice; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Mucin-2; Mutation; Neoplasms, Cystic, Mucinous, and Serous; Phosphatidylinositol 3-Kinases; Primary Cell Culture; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Sulfonamides; Xenograft Model Antitumor Assays

2020
The evolutionarily conserved MAPK/Erk signaling promotes ancestral T-cell immunity in fish via c-Myc-mediated glycolysis.
    The Journal of biological chemistry, 2020, 03-06, Volume: 295, Issue:10

    Topics: Adaptive Immunity; Aeromonas hydrophila; Animals; Cichlids; Evolution, Molecular; Extracellular Signal-Regulated MAP Kinases; Fish Diseases; Fish Proteins; Glycolysis; Interferon-gamma; Lymphocyte Activation; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Phylogeny; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-raf; Pyridones; Pyrimidinones; T-Lymphocytes

2020
Adjuvant therapy for melanoma: how to choose?
    The Lancet. Oncology, 2020, Volume: 21, Issue:3

    Topics: Biomarkers; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

2020
Trametinib and Dabrafenib in histiocytic sarcoma transdifferentiated from chronic lymphocytic leukemia with a K-RAS and a unique BRAF mutation.
    Annals of hematology, 2020, Volume: 99, Issue:3

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cell Transdifferentiation; Head and Neck Neoplasms; Histiocytic Sarcoma; Humans; Imidazoles; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Oximes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones

2020
Secondary histiocytic sarcoma with BRAF
    Pediatric blood & cancer, 2020, Volume: 67, Issue:5

    Topics: Amino Acid Substitution; Histiocytic Sarcoma; Humans; Imidazoles; Infant; Male; Mutation, Missense; Neoplasms, Second Primary; Oximes; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2020
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 06-01, Volume: 26, Issue:11

    Paired fresh tumor biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM colorectal cancer enrolled in a phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS).. Confirmed response rates, median PFS, and median overall survival (OS) were higher in BM1 subtype patients compared with BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, whereas cell-cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell-cycle signatures revealed that BM subtype encompasses the majority of the effect.. BM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colorectal Neoplasms; ErbB Receptors; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; MAP Kinase Kinase 1; Mutation; Oximes; Panitumumab; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

2020
Induced sarcoid-like reactions in patients with metastatic melanoma treated with dabrafenib and trametinib: a monocentric retrospective study.
    Melanoma research, 2020, Volume: 30, Issue:3

    Combined BRAF and MEK inhibition is one of the first-line treatment strategies for patients with advanced BRAF-mutant melanoma. Sarcoid-like reactions (SLRs) have occasionally been described with melanoma systemic treatments such as immunotherapy or the BRAF inhibitor vemurafenib, but very few cases have been reported with dabrafenib and trametinib. Our aim was to better characterize SLR induced by this combination. We conducted a monocentric retrospective observational study among patients treated with dabrafenib and trametinib for BRAF-mutant advanced melanoma from January 2015 to March 2019. Patients presenting with histologically proven SLR were included. We also searched Medline database for all reported cases of SLR induced by targeted therapy. Of 63 patients on dabrafenib/trametinib combination, seven were diagnosed with a SLR. They all had specific cutaneous involvement, and one also displayed mediastinal and salivary glands involvement. None required systemic corticosteroids or dabrafenib/trametinib discontinuation. Three of them (43%) reached melanoma complete remission and are still on targeted therapy; and four patients progressed and died. A literature review yielded 22 additional cases of SLR induced by targeted therapy: the main affected organ was the skin, 11 patients (50%) had systemic involvement, five patients (23%) required systemic corticosteroids to reach partial or complete remission of SLR, 12 (55%) reached partial or complete response of melanoma while six (27%) progressed. BRAF and MEK inhibitors are potential triggers of SLR, although pathological mechanisms remain unclear. The mainstay of treatment is systemic or topical corticotherapy; targeted therapy discontinuation is usually not necessary.

    Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Sarcoidosis; Skin Neoplasms

2020
Reduced doses of dabrafenib and trametinib combination therapy for BRAF V600E-mutant non-small cell lung cancer prevent rhabdomyolysis and maintain tumor shrinkage: a case report.
    BMC cancer, 2020, Feb-24, Volume: 20, Issue:1

    A BRAF V600E mutation is found as driver oncogene in patients with non-small cell lung cancer. Although combined treatment with dabrafenib and trametinib is highly effective, the efficacy of reduced doses of the drugs in combination therapy has not yet been reported.. A Japanese man in his mid-sixties was diagnosed with unresectable lung adenocarcinoma and was unresponsive to cytotoxic chemotherapy and immune checkpoint inhibitors. The BRAF V600E mutation was detected by next generation sequencing, and the patient was subjected to treatment with dabrafenib and trametinib in combination. Although the treatment reduced the tumor size, he experienced myalgia and muscle weakness with elevated serum creatine kinase and was diagnosed with rhabdomyolysis induced by dabrafenib and trametinib. After the patient recovered from rhabdomyolysis, the treatment doses of dabrafenib and trametinib were reduced, which prevented further rhabdomyolysis and maintained tumor shrinkage.. The reduction of the doses of dabrafenib and trametinib was effective in the treatment of BRAF V600E-mutant NSCLC, and also prevented the incidence of rhabdomyolysis.

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Off-Label Use; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Rhabdomyolysis; Treatment Outcome

2020
Treatment of metastasized melanoma with combined checkpoint inhibition in a patient with highly active multiple sclerosis.
    The Journal of dermatology, 2020, Volume: 47, Issue:5

    Topics: Adult; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemotherapy, Adjuvant; Glucocorticoids; Humans; Imidazoles; Interferon-beta; Male; Melanoma; Multiple Sclerosis; Neoplasm Recurrence, Local; Oximes; Polyethylene Glycols; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2020
Establishment of a novel human cell line retaining the characteristics of the original pancreatic adenocarcinoma, and evaluation of MEK as a therapeutic target.
    International journal of oncology, 2020, Volume: 56, Issue:3

    Pancreatic cancer is a lethal solid malignancy with limited therapeutic options. The development of novel therapeutic drugs requires adequate new cell line models. A new pancreatic cancer cell line, designated PDXPC1, was established from one pancreatic ductal adenocarcinoma (PDAC) patient‑derived xenograft. The PDXPC1 cells were stably cultured for >2 years and had a stable short tandem repeat profile. The PDXPC1 cell line retained the key mutations of the primary tumor, along with the epithelial origin and other important protein expression. The PDXPC1 cells induced rapid in vivo tumor growth, both subcutaneously and orthotopically, in a mouse model with an elevated CA199 level. The PDXPC1 cells showed weak growth, invasion and migration potency compared to another pancreatic cancer cell line, but were relatively resistant to multiple anti‑cancer drugs. Interestingly, the MEK inhibitor trametinib significantly inhibited the proliferation of PDXPC1 cells, and not that of Panc‑1 cells, by inactivating MEK/ERK/MYC signaling and activating the apoptotic pathway via Bcl‑2 degradation. In conclusion, the PDXPC1 cell line, capturing the major characteristics of the primary tumor, may be a suitable tool for studying the underlying mechanisms of chemo‑resistance in PDAC and developing new targeted therapeutic options.

    Topics: Animals; Carcinoma, Pancreatic Ductal; Cell Culture Techniques; Cell Proliferation; Cell Survival; Female; Humans; Mice; Mutation; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2020
Granulomatosis with polyangiitis in a patient treated with dabrafenib and trametinib for BRAF V600E positive lung adenocarcinoma.
    BMC cancer, 2020, Mar-04, Volume: 20, Issue:1

    Dabrafenib and trametinib combination therapy is approved for the treatment of patients with BRAF V600E positive tumors including melanoma and lung cancer. The effect of BRAF and MEK inhibitors on the immune system is not fully understood although a number of case reports indicate autoimmune side effects related to the use of these drugs. Here, we discuss a case of a patient diagnosed with granulomatosis with polyangiitis (GPA) shortly after starting treatment with dabrafenib and trametinib for BRAF V600E positive metastatic lung adenocarcinoma.. A 57 years old female patient was diagnosed with recurrent lung adenocarcinoma following initial lobectomy for early stage disease. A BRAF V600E mutation was identified at the time of recurrence and she received combination dabrafenib and trametinib therapy. Shortly after commencement of treatment, she developed persistent fevers necessitating withholding both drugs. Pyrexia continued and was followed by left vision loss and acute kidney injury. Further rheumatological workup led to the unifying diagnosis of GPA. The patient was then treated with rituximab for GPA to the present date while all antineoplastic drugs were held. Lung cancer oligoprogression was addressed with radiation therapy and has not required further systemic treatment whereas GPA has been controlled to-date with rituximab.. This case report raises awareness among clinicians treating patients with lung cancer for the possibility of triggering a flare of autoimmune diseases like GPA in patients with BRAF V600E positive lung cancer receiving treatment with BRAF directed therapy.

    Topics: Adenocarcinoma of Lung; Amino Acid Substitution; Antineoplastic Combined Chemotherapy Protocols; Female; Granulomatosis with Polyangiitis; Humans; Imidazoles; Lung Neoplasms; Middle Aged; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Rituximab; Treatment Outcome

2020
Apparent darkening of scalp hair related to pili multigemini Following dabrafenib and trametinib.
    Dermatology online journal, 2020, Jan-15, Volume: 26, Issue:1

    The combination of dabrafenib and trametinib is an important immunotherapy option for patients with BRAF V600 mutation-positive melanoma. This regimen has been reported to cause cutaneous eruptions. However, hair dysmorphology is not a reported side effect to these or any other medications to date. Herein, we highlight a case of pili multigemini formation in a patient with stage IV melanoma receiving treatment with dabrafenib and trametinib and the corresponding clinical findings.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Hair; Hair Diseases; Hair Follicle; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Pigmentation Disorders; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

2020
The effect of MEK1/2 inhibitors on cisplatin-induced acute kidney injury (AKI) and cancer growth in mice.
    Cellular signalling, 2020, Volume: 71

    Topics: Acute Kidney Injury; Animals; Apoptosis; Blood Urea Nitrogen; Butadienes; Cell Proliferation; Cisplatin; Kidney; Lipocalin-2; Lung Neoplasms; MAP Kinase Signaling System; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Neoplasm Proteins; Nitriles; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Tumor Burden

2020
Constitutive Activation of RAS/MAPK Pathway Cooperates with Trisomy 21 and Is Therapeutically Exploitable in Down Syndrome B-cell Leukemia.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 07-01, Volume: 26, Issue:13

    Children with Down syndrome (constitutive trisomy 21) that develop acute lymphoblastic leukemia (DS-ALL) have a 3-fold increased likelihood of treatment-related mortality coupled with a higher cumulative incidence of relapse, compared with other children with B-cell acute lymphoblastic leukemia (B-ALL). This highlights the lack of suitable treatment for Down syndrome children with B-ALL.. To facilitate the translation of new therapeutic agents into clinical trials, we built the first preclinical cohort of patient-derived xenograft (PDX) models of DS-ALL, comprehensively characterized at the genetic and transcriptomic levels, and have proven its suitability for preclinical studies by assessing the efficacy of drug combination between the MEK inhibitor trametinib and conventional chemotherapy agents.. Altogether, using novel and suitable PDX models, this study indicates that RAS/MAPK pathway inhibition represents a promising strategy to improve the outcome of Down syndrome children with B-cell precursor leukemia.

    Topics: Animals; Computational Biology; Disease Models, Animal; Disease Susceptibility; Down Syndrome; Gene Expression Profiling; Humans; Immunophenotyping; Leukemia, B-Cell; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinases; Oncogenes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; ras Proteins; Signal Transduction

2020
Combined targeting of MEK and the glucocorticoid receptor for the treatment of RAS-mutant multiple myeloma.
    BMC cancer, 2020, Mar-30, Volume: 20, Issue:1

    Multiple myeloma (MM) remains incurable despite recent therapeutic advances. RAS mutations are frequently associated with relapsed/refractory disease. Efforts to target the mitogen-activated protein kinase (MAPK) pathway with the MEK inhibitor, trametinib (Tra) have been limited by toxicities and the development of resistance. Dexamethasone (Dex) is a corticosteroid commonly used in clinical practice, to enhance efficacy of anti-myeloma therapy. Therefore, we hypothesised that the combination of Tra and Dex would yield synergistic activity in RAS-mutant MM.. The response of human MM cell lines to drug treatment was analysed using cell proliferation assays, Western blotting, Annexin V and propidium iodide staining by flow cytometry and reverse phase protein arrays. The efficacy of trametinib and dexamethasone treatment in the MM.1S xenograft model was assessed by measuring tumor volume over time.. Overall Tra/Dex demonstrates antiproliferative activity in RAS-mutant MM cell lines associated with suppression of pro-survival PDK1 signalling and engagement of apoptotic pathways. Our data support further investigation of this combination in RAS-mutant MM.

    Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Dexamethasone; Drug Synergism; Drug Therapy, Combination; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; MAP Kinase Kinase Kinases; Multiple Myeloma; Mutation; Pyridones; Pyrimidinones; Pyruvate Dehydrogenase Acetyl-Transferring Kinase; ras Proteins; Receptors, Glucocorticoid; Signal Transduction

2020
Kinome Profiling of NF1-Related MPNSTs in Response to Kinase Inhibition and Doxorubicin Reveals Therapeutic Vulnerabilities.
    Genes, 2020, 03-20, Volume: 11, Issue:3

    Neurofibromatosis Type 1 (NF1)-related Malignant Peripheral Nerve Sheath Tumors (MPNST) are highly resistant sarcomas that account for significant mortality. The mechanisms of therapy resistance are not well-understood in MPNSTs, particularly with respect to kinase inhibition strategies. In this study, we aimed to quantify the impact of both the genomic context and targeted therapy on MPNST resistance using reverse phase phosphoproteome array (RPPA) analysis. We treated tumorgrafts from three genetically engineered mouse models using MET (capmatinib) and MEK (trametinib) inhibitors and doxorubicin, and assessed phosphosignaling at 4 h, 2 days, and 21 days. Baseline kinase signaling in our mouse models recapitulated an MET-addicted state (NF1-MET), P53 mutation (NF1-P53), and HGF overexpression (NF1). Following perturbation with the drug, we observed broad and redundant kinome adaptations that extended well beyond canonical RAS/ERK or PI3K/AKT/mTOR signaling. MET and MEK inhibition were both associated with an initial inflammatory response mediated by kinases in the JAK/STAT pathway and NFkB. Growth signaling predominated at the 2-day and 21-day time points as a result of broad RTK and intracellular kinase activation. Interestingly, AXL and NFkB were strongly activated at the 2-day and 21-day time points, and tightly correlated, regardless of the treatment type or genomic context. The degree of kinome adaptation observed in innately resistant tumors was significantly less than the surviving fractions of responsive tumors that exhibited a latency period before reinitiating growth. Lastly, doxorubicin resistance was associated with kinome adaptations that strongly favored growth and survival signaling. These observations confirm that MPNSTs are capable of profound signaling plasticity in the face of kinase inhibition or DNA damaging agent administration. It is possible that by targeting AXL or NFkB, therapy resistance can be mitigated.

    Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Doxorubicin; Extracellular Signal-Regulated MAP Kinases; Imidazoles; MAP Kinase Signaling System; Mice; Mice, SCID; Nerve Sheath Neoplasms; Neurofibromin 1; NF-kappa B; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proteome; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; ras Proteins; STAT Transcription Factors; Topoisomerase II Inhibitors; TOR Serine-Threonine Kinases; Triazines

2020
Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib.
    International journal of molecular sciences, 2020, Mar-21, Volume: 21, Issue:6

    Activation of the mitogen-activated protein kinase (MAPK) signaling pathway regulated by human MAP kinase 1 (MEK1) is associated with the carcinogenesis and progression of numerous cancers. In addition, two active mutations (P124S and E203K) have been reported to enhance the activity of MEK1, thereby eventually leading to the tumorigenesis of cancer. Trametinib is an MEK1 inhibitor for treating EML4-ALK-positive, EGFR-activated, and KRAS-mutant lung cancers. Therefore, in this study, molecular docking and molecular dynamic (MD) simulations were performed to explore the effects of inactive/active mutations (A52V/P124S and E203K) on the conformational changes of MEK1 and the changes in the interaction of MEK1 with trametinib. Moreover, steered molecular dynamic (SMD) simulations were further utilized to compare the dissociation processes of trametinib from the wild-type (WT) MEK1 and two active mutants (P124S and E203K). As a result, trametinib had stronger interactions with the non-active MEK1 (WT and A52V mutant) than the two active mutants (P124S and E203K). Moreover, two active mutants may make the allosteric channel of MEK1 wider and shorter than that of the non-active types (WT and A52V mutant). Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.

    Topics: Allosteric Site; Antineoplastic Agents; Catalysis; Hydrogen Bonding; Ligands; MAP Kinase Kinase 1; Molecular Docking Simulation; Mutation; Protein Binding; Protein Conformation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Static Electricity; Thermodynamics

2020
Treatment of Trametinib-Associated Folliculitis Eruption With Fluconazole.
    JAMA dermatology, 2020, 06-01, Volume: 156, Issue:6

    Topics: Administration, Oral; Antifungal Agents; Biopsy; Drug Eruptions; Fluconazole; Folliculitis; Follow-Up Studies; Humans; Malassezia; Neurofibroma, Plexiform; Neurofibromatosis 1; Pyridones; Pyrimidinones; Retrospective Studies; Skin; Treatment Outcome

2020
[A woman with a skin lesion suspected for melanoma].
    Nederlands tijdschrift voor geneeskunde, 2020, 02-27, Volume: 164

    We saw a 59-year-old patient who was treated with dabrafenib and trametinib because of metastatic melanoma. She had an asymptomatic, black-blue macula in the excision scar. Histopathology showed tumoral melanosis. This is an histological term for dermal aggregates of melanophages, associated with regression of melanoma.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Cicatrix; Female; Humans; Imidazoles; Melanoma; Melanosis; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Diseases; Skin Neoplasms

2020
Limited antitumor activity of combined BET and MEK inhibition in neuroblastoma.
    Pediatric blood & cancer, 2020, Volume: 67, Issue:6

    The treatment of high-risk neuroblastoma continues to present a formidable challenge to pediatric oncology. Previous studies have shown that Bromodomain and extraterminal (BET) inhibitors can inhibit MYCN expression and suppress MYCN-amplified neuroblastoma in vivo. Furthermore, alterations within RAS-MAPK (mitogen-activated protein kinase) signaling play significant roles in neuroblastoma initiation, maintenance, and relapse, and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors demonstrate efficacy in subsets of neuroblastoma preclinical models. Finally, hyperactivation of RAS-MAPK signaling has been shown to promote resistance to BET inhibitors. Therefore, we examined the antitumor efficacy of combined BET/MEK inhibition utilizing I-BET726 or I-BET762 and trametinib in high-risk neuroblastoma.. Utilizing a panel of genomically annotated neuroblastoma cell line models, we investigated the in vitro effects of combined BET/MEK inhibition on cell proliferation and apoptosis. Furthermore, we evaluated the effects of combined inhibition in neuroblastoma xenograft models.. Combined BET and MEK inhibition demonstrated synergistic effects on the growth and survival of a large panel of neuroblastoma cell lines through augmentation of apoptosis. A combination therapy slowed tumor growth in a non-MYCN-amplified, NRAS-mutated neuroblastoma xenograft model, but had no efficacy in an MYCN-amplified model harboring a loss-of-function mutation in NF1.. Combinatorial BET and MEK inhibition was synergistic in the vast majority of neuroblastoma cell lines in the in vitro setting but showed limited antitumor activity in vivo. Collectively, these data do not support clinical development of this combination in high-risk neuroblastoma.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Benzodiazepines; Cell Proliferation; Female; Humans; MAP Kinase Kinase 1; Mice; Mice, SCID; Neuroblastoma; Proteins; Pyridones; Pyrimidinones; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2020
Exploiting evolutionary steering to induce collateral drug sensitivity in cancer.
    Nature communications, 2020, 04-21, Volume: 11, Issue:1

    Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 10

    Topics: Antineoplastic Agents; Clonal Evolution; Computational Biology; Computer Simulation; Drug Resistance, Neoplasm; Evolution, Molecular; Gefitinib; Genotype; Humans; Lung Neoplasms; Models, Theoretical; Molecular Medicine; Pyridones; Pyrimidinones; Stochastic Processes

2020
Establishment and characterization of a cell line and patient-derived xenograft (PDX) from peritoneal metastasis of low-grade serous ovarian carcinoma.
    Scientific reports, 2020, 04-21, Volume: 10, Issue:1

    Peritoneal spread indicates poor prognosis in patients with serous ovarian carcinoma (SOC) and is generally treated by surgical cytoreduction and chemotherapy. Novel treatment options are urgently needed to improve patient outcome. Clinically relevant cell lines and patient-derived xenograft (PDX) models are of critical importance to therapeutic regimen evaluation. Here, a PDX model was established, by orthotopic engraftment after subperitoneal tumor slurry injection of low-grade SOC, resulting in an early-stage transplantable peritoneal metastasis (PM)-PDX model. Histology confirmed the micropapillary and cribriform growth pattern with intraluminal tumor budding and positivity for PAX8 and WT1. PM-PDX dissociated cells show an epithelial morphotype with a 42 h doubling time and 40% colony forming efficiency, they are low sensitive to platinum derivatives and highly sensitive to paclitaxel (IC50: 6.3 ± 2.2 nM, mean ± SEM). The patient primary tumor, PM, PM-PDX and derived cell line all show a KRAS c.35 G > T (p.(Gly12Val)) mutation and show sensitivity to the MEK inhibitor trametinib in vitro (IC50: 7.2 ± 0.5 nM, mean ± SEM) and in the PM mouse model. These preclinical models closely reflecting patient tumors are useful to further elucidate LGSOC disease progression, therapy response and resistance mechanisms.

    Topics: Animals; Cell Line, Tumor; Cystadenocarcinoma, Serous; Female; Humans; Mice, SCID; Microsatellite Repeats; Mutation; Ovarian Neoplasms; Peritoneal Neoplasms; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2020
Huai Qi Huang-induced Apoptosis via Down-regulating PRKCH and Inhibiting RAF/MEK/ERK Pathway in Ph
    Current medical science, 2020, Volume: 40, Issue:2

    Imatinib mesylate (IM) is the first-line treatment for Philadelphia (Ph) chromosomal positive leukemia by inhibiting phosphorylation of substrates via binding to the ABL kinase domain. Because of the drug resistance, side effects and the high cost of IM, it is necessary to find anti-cancer drugs with relatively low toxicity and cost, and enhanced efficacy, such as traditional Chinese medicines (TCMs). As one of TCMs, Huai Qi Huang (HQH) was chosen to treat BV173 and K562 cells. Various concentrations of HQH were added to cells for 24-72 h. Co-treatment of HQH and trametinib, an MEK inhibitor, was used to verify the synergistic effects on cell viability and apoptosis. Knockdown and overexpression of mitogen-activated protein kinase kinase 4 (MEK4) were implemented to demonstrate the role of MEK in cell apoptosis. Cell viability and apoptosis were measured by cell counting kit-8 assay (CCK8) and flow cytometry, respectively. Western blotting and real-time quantitative PCR (RT-qPCR) were used to assess protein and mRNA expression levels, respectively. The results showed that HQH inhibited survival and promoted apoptosis of BV173 and K562 cells in a dose-dependent manner, accompanied with down-regulation of PRKCH mRNA as well as CRAF, MEK4, phospho-ERK (pERK) and BCL2 proteins, and up-regulation of cleaved caspase3 protein. Co-treatment of HQH and trametinib had a synergistic effect on inhibiting survival and promoting apoptosis. MEK4 knockdown increased apoptosis, and had a synergistic effect with HQH. In contrast, MEK4 overexpression decreased apoptosis, and had the opposite effect with HQH. Collectively, the results of this study may identify a therapeutic mechanism of HQH on promoting apoptosis, and provide a potential option for treatment of Ph

    Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Down-Regulation; Drug Synergism; Drugs, Chinese Herbal; Gene Expression Regulation, Neoplastic; Humans; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; MAP Kinase Signaling System; Protein Kinase C; Pyridones; Pyrimidinones

2020
Trametinib potentiates TRAIL-induced apoptosis via FBW7-dependent Mcl-1 degradation in colorectal cancer cells.
    Journal of cellular and molecular medicine, 2020, Volume: 24, Issue:12

    Trametinib is a MEK1/2 inhibitor and exerts anticancer activity against a variety of cancers. However, the effect of Trametinib on colorectal cancer (CRC) is not well understood. In the current study, our results demonstrate the ability of sub-toxic doses of Trametinib to enhance TRAIL-mediated apoptosis in CRC cells. Our findings also indicate that Trametinib and TRAIL activate caspase-dependent apoptosis in CRC cells. Moreover, Mcl-1 overexpression can reduce apoptosis in CRC cells treated with Trametinib with or without TRAIL. We further demonstrate that Trametinib degrades Mcl-1 through the proteasome pathway. In addition, GSK-3β phosphorylates Mcl-1 at S159 and promotes Mcl-1 degradation. The E3 ligase FBW7, known to polyubiquitinate Mcl-1, is involved in Trametinib-induced Mcl-1 degradation. Taken together, these results provide the first evidence that Trametinib enhances TRAIL-mediated apoptosis through FBW7-dependent Mcl-1 ubiquitination and degradation.

    Topics: Apoptosis; Cell Line, Tumor; Colorectal Neoplasms; Down-Regulation; F-Box-WD Repeat-Containing Protein 7; Glycogen Synthase Kinase 3 beta; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Proteasome Endopeptidase Complex; Protein Binding; Proteolysis; Pyridones; Pyrimidinones; TNF-Related Apoptosis-Inducing Ligand; Ubiquitin; Ubiquitination

2020
The limitations of targeting MEK signalling in Glioblastoma therapy.
    Scientific reports, 2020, 05-04, Volume: 10, Issue:1

    Glioblastoma (GB) is a highly aggressive, difficult to treat brain tumour. Successful treatment, consisting of maximal safe tumour de-bulking, followed by radiotherapy and treatment with the alkylating agent Temozolomide (TMZ), can extend patient survival to approximately 15 months. Combination treatments based on the inhibition of the PI3K pathway, which is the most frequently activated signalling cascade in GB, have so far only shown limited therapeutic success. Here, we use the clinically approved MEK inhibitor Trametinib to investigate its potential use in managing GB. Trametinib has a strong anti-proliferative effect on established GB cell lines, stem cell-like cells and their differentiated progeny and while it does not enhance anti-proliferative and cell death-inducing properties of the standard treatment, i.e. exposure to radiation or TMZ, neither does MEK inhibition block their effectiveness. However, upon MEK inhibition some cell populations appear to favour cell-substrate interactions in a sprouting assay and become more invasive in the Chorioallantoic Membrane assay, which assesses cell penetration into an organic membrane. While this increased invasion can be modulated by additional inhibition of the PI3K signalling cascade, there is no apparent benefit of blocking MEK compared to targeting PI3K.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Brain Neoplasms; Cell Adhesion; Cell Death; Cell Line, Tumor; Cell Proliferation; Chorioallantoic Membrane; Drug Screening Assays, Antitumor; Glioblastoma; Humans; MAP Kinase Kinase 1; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphatidylinositol 3-Kinases; Phosphorylation; Pyridones; Pyrimidinones; Signal Transduction; Temozolomide; Translational Research, Biomedical

2020
Dual Fulvestrant-Trametinib Therapy in Recurrent Low-Grade Serous Ovarian Cancer.
    The oncologist, 2020, Volume: 25, Issue:7

    Low-grade serous ovarian carcinoma (LGSOC) is known to exhibit chemoresistance. Effective treatment options for recurrent disease are few and often limited to hormone antagonism. Combination of endocrine therapies with MEK-inhibitors displays synergism in preclinical ovarian cancer models, however. This brief communication presents the use of combination anti-estrogenic and MEK-inhibitor therapies, fulvestrant and trametinib, as treatment in a heavily pretreated patient with estrogen receptor-positive, recurrent LGSOC. The dual-therapy regimen was well tolerated and appeared to confer 9 months of progression-free survival. Further investigation is warranted to explore this effect.

    Topics: Female; Fulvestrant; Humans; Ovarian Neoplasms; Pyridones; Pyrimidinones

2020
Re: "Complete Surgical Resection Following Neoadjuvant Dabrafenib Plus Trametinib in
    Thyroid : official journal of the American Thyroid Association, 2020, Volume: 30, Issue:8

    Topics: Humans; Imidazoles; Neoadjuvant Therapy; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

2020
A combinatorial strategy for overcoming primary and acquired resistance of MEK inhibition in colorectal cancer.
    Experimental cell research, 2020, 08-01, Volume: 393, Issue:1

    Compared with traditional chemotherapeutic drugs, targeted therapeutic medicine has the advantages of high efficacy and less toxic side effects. However, in clinical practice for treatment of colorectal cancer, the primary and acquired resistance of these medicines limits their effectiveness in targeted therapy, therefore impedes the development of precision medicine and personalized therapy. Currently, there are limited number of drugs for targeted therapy of colorectal cancer, mainly monoclonal antibodies against EGFR or VEGFR inhibitors. Trametinib, a MEK inhibitor, has been applied in melanoma patient successfully, but not been used in clinical treatment of colorectal cancer because of its drug resistance. To identify the resistance mechanism of colorectal cancer cells to trametinib and find useful chemical combination to overcome the resistance, we screened primary and acquired cell line first and then tested multiple synergistic drug combinations by using the Chou-Talalay method. We obtained the primary resistant cell lines SW480, CW-2 and the acquired drug-resistant cell line RKO-R as well as a synergistic combination of trametinib and GSK2126458. This combination inhibits the colony formation of colorectal cancer cells and the growth of xenograft tumors in nude mice. Mechanistic analysis showed that trametinib can activate the alternative PI3K-AKT signaling pathway while inhibiting the MAPK pathway, which may be one of the molecular mechanisms of primary and acquired trametinib tolerance in colorectal cancer cells. Importantly, this bypass activation can be blocked by GSK2126458. These results suggest that a combination of trametinib and GSK2126458 is an effective approach for treating colorectal cancer resistance to trametinib.

    Topics: Animals; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Resistance, Neoplasm; Humans; Melanoma; Mice, Inbred BALB C; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2020
Hair Changes During Treatment With Trametinib.
    Actas dermo-sifiliograficas, 2020, Volume: 111, Issue:5

    Topics: Pyridones; Pyrimidinones

2020
Bim, Puma and Noxa upregulation by Naftopidil sensitizes ovarian cancer to the BH3-mimetic ABT-737 and the MEK inhibitor Trametinib.
    Cell death & disease, 2020, 05-18, Volume: 11, Issue:5

    Ovarian cancer represents the first cause of mortality from gynecologic malignancies due to frequent chemoresistance occurrence. Increasing the [BH3-only Bim, Puma, Noxa proapoptotic]/[Bcl-x

    Topics: Apoptosis Regulatory Proteins; bcl-X Protein; Biphenyl Compounds; Female; Humans; Mitogen-Activated Protein Kinase Kinases; Naphthalenes; Nitrophenols; Ovarian Neoplasms; Piperazines; Pyridones; Pyrimidinones; Sulfonamides; Up-Regulation

2020
Identification of a Triple Drug Combination That Is Synergistically Cytotoxic for Triple-Negative Breast Cancer Cells Using a Novel Combination Discovery Approach.
    SLAS discovery : advancing life sciences R & D, 2020, Volume: 25, Issue:8

    Triple-negative breast cancer (TNBC) is a very aggressive form of breast cancer with few molecularly targeted therapies. We used a novel unbiased approach to identify higher-order synergistic or enhancer combinations of marketed kinase inhibitor drugs that inhibit cell viability of TNBC cell lines. We mixed all 33 kinase-targeted drugs on the market at the time of this study, which allowed for all possible combinations to exist in the initial mixture. A kinase inhibitor group dropout approach was used to identify active groups and then single active drugs. After only three rounds of deconvolution, we identified five single drugs to test further. After further testing, we focused on one novel subset consisting of three kinase inhibitor drugs: dasatinib, afatinib, and trametinib (DAT) that target src family kinases, HER2/EGFR, and MEK, respectively. The DAT combination potently inhibited the proliferation of three TNBC cell lines and modestly inhibited a fourth. However, it was not significantly more potent or synergistic than other two drug combinations of these drugs. The cytotoxic activities of all possible combinations of these three drugs were also analyzed. Compared with all two-way combinations, the three-way DAT combination generated the most cytotoxicity and the highest synergies for two of the four cell lines tested, with possibly mild synergy in a third cell line. These data indicated that the DAT combination should be evaluated for efficacy in an in vivo model of TNBC and may provide a novel combination of existing drugs for the treatment of a subset of TNBC cases.

    Topics: Afatinib; Animals; Cell Proliferation; Dasatinib; Drug Combinations; ErbB Receptors; Female; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptor, ErbB-2; src-Family Kinases; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

2020
SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy.
    Cancer cell, 2020, 06-08, Volume: 37, Issue:6

    Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic.

    Topics: Animals; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Proliferation; Chromatin; Drug Resistance, Neoplasm; Female; Histocompatibility Antigens; Histone Deacetylases; Histone-Lysine N-Methyltransferase; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Methyltransferases; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Small Molecule Libraries; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2020
MEK inhibition overcomes everolimus resistance in gastric cancer.
    Cancer chemotherapy and pharmacology, 2020, Volume: 85, Issue:6

    Although substantial evidence has shown that the mammalian target of rapamycin (mTOR) pathway is an important therapeutic target in gastric cancer, the overall response rates in patients to mTOR inhibitor everolimus have been less than initially expected. We hypothesized that the limited efficacy of everolimus in gastric cancer is due to the activation of extracellular signal-regulated kinase (ERK).. ERK activation was investigated using western blot. The effects of dual inhibition of ERK and mTOR via genetic and pharmacological approaches were determined using cellular assays and xenograft mouse model.. We observed the decreased phosphorylation of mTOR, rS6, and 4EBP1 and increased phosphorylation of ERK and p90RSK in gastric cancer cells exposed to everolimus at clinically relevant concentration. Using both in vitro cell culture assays and in vivo xenograft mouse model, we found that trametinib overcame everolimus resistance by either effectively targeting resistant cells or further enhancing everolimus' efficacy in sensitive cells. Mechanism studies confirmed that trametinib overcame everolimus resistance via specifically inhibiting ERK and regulating ERK-mediated Bcl-2 family proteins in gastric cancer cells.. Inhibition of mTOR pathway can induce "paradoxical" activation of ERK in gastric cancer, and this activation can be reversed by trametinib. Since both drugs are clinically available, our findings might accelerate the initiation of clinical trials on gastric cancer using everolimus and trametinib combination.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Drug Resistance, Neoplasm; Everolimus; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; Stomach Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2020
Primary CNS Metastatic BRAF-mutated Lung Adenocarcinoma With Complete Intracranial Response to BRAF/MEK Inhibition.
    Clinical lung cancer, 2020, Volume: 21, Issue:6

    Topics: Adenocarcinoma of Lung; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Combined Modality Therapy; Humans; Imidazoles; Lung Neoplasms; MAP Kinase Kinase 1; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiosurgery

2020
Combined osimertinib, dabrafenib and trametinib treatment for advanced non-small-cell lung cancer patients with an osimertinib-induced BRAF V600E mutation.
    Lung cancer (Amsterdam, Netherlands), 2020, Volume: 146

    Previous studies have reported an acquiredBRAF V600E mutation as a potential resistance mechanism to osimertinib treatment in advanced NSCLC patients with an activating mutation in EGFR. However, the therapeutic effect of combining dabrafenib and trametinib with osimertinib remains unclear. Here we report treatment efficacy in two cases with acquired BRAF V600E mutations.. Two patients with anEGFR exon 19 deletion and a T790 M mutation, both treated with osimertinib, acquired a BRAF V600E mutation at disease progression. Following the recommendation of the molecular tumor board, a concurrent combination of dabrafenib and trametinib plus osimertinib was administered.. Because of toxicity, one patient ultimately received a reduced dose of dabrafenib and trametinib combined with a normal dose of osimertinib. Clinical response in this patient lasted for 13.4 months. Re-biopsy upon tumor progression revealed loss ofBRAF V600E and emergence of EGFR C797S. The other patient, treated with full doses of the combined therapy, had progression with metastases in lung and brain one month after starting therapy.. BRAF V600E may be a resistance mechanism induced by osimertinib in EGFR-mutated advanced NSCLC. Combined treatment using dabrafenib/trametinib concurrently with osimertinib needs to be explored for osimertinib-induced BRAF V600E mutation.

    Topics: Acrylamides; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2020
Acquired BRAF N581S mutation mediated resistance to gefitinib and responded to dabrafenib plus trametinib.
    Lung cancer (Amsterdam, Netherlands), 2020, Volume: 146

    BRAFG469A and V600E were reported as the mechanisms of acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer patients. Here, we described a rare case of BRAF N581S after gefitinib resistance and response to BRAF inhibitor plus MEK inhibitor.. Next-generation sequencing (NGS) was performed on the tumor tissue and plasma samples of a patient with metastatic lung adenocarcinoma harboring EGFR exon 19 deletion (EGFR 19del).. EGFR 19del and MET amplification was detected after resistance to the initial gefitinib therapy. After 9 months of treatment with gefitinib plus crizotinib, the disease progressed again. NGS revealed the known EGFR 19del and a BRAF N581S missense mutation after progression. The patient obtained durable clinical benefit upon treatment with dabrafenib plus trametinib, achieving a progression-free survival (PFS) of more than 33 months.. BRAF N581S mutation could be explored as one kind of mechanism of acquired resistance to EGFR-TKIs. Combined inhibition of BRAF and MEK is a potential therapeutic strategy.

    Topics: Carcinoma, Non-Small-Cell Lung; Gefitinib; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2020
Effective drug treatment identified by in vivo screening in a transplantable patient-derived xenograft model of chronic myelomonocytic leukemia.
    Leukemia, 2020, Volume: 34, Issue:11

    To establish novel and effective treatment combinations for chronic myelomonocytic leukemia (CMML) preclinically, we hypothesized that supplementation of CMML cells with the human oncogene Meningioma 1 (MN1) promotes expansion and serial transplantability in mice, while maintaining the functional dependencies of these cells on their original genetic profile. Using lentiviral expression of MN1 for oncogenic supplementation and transplanting transduced primary mononuclear CMML cells into immunocompromised mice, we established three serially transplantable CMML-PDX models with disease-related gene mutations that recapitulate the disease in vivo. Ectopic MN1 expression was confirmed to enhance the proliferation of CMML cells, which otherwise did not engraft upon secondary transplantation. Furthermore, MN1-supplemented CMML cells were serially transplantable into recipient mice up to 5 generations. This robust engraftment enabled an in vivo RNA interference screening targeting CMML-related mutated genes including NRAS, confirming that their functional relevance is preserved in the presence of MN1. The novel combination treatment with azacitidine and the MEK-inhibitor trametinib additively inhibited ERK-phosphorylation and thus depleted the signal from mutated NRAS. The combination treatment significantly prolonged survival of CMML mice compared to single-agent treatment. Thus, we identified the combination of azacitidine and trametinib as an effective treatment in NRAS-mutated CMML and propose its clinical development.

    Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Clonal Evolution; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Synergism; Female; GTP Phosphohydrolases; Humans; Leukemia, Myelomonocytic, Chronic; Membrane Proteins; Mice; Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptor, Notch1; RNA, Small Interfering; Xenograft Model Antitumor Assays

2020
    Cancer research, 2020, 08-15, Volume: 80, Issue:16

    Survival for high-risk neuroblastoma remains poor and treatment for relapsed disease rarely leads to long-term cures. Large sequencing studies of neuroblastoma tumors from diagnosis have not identified common targetable driver mutations other than the 10% of tumors that harbor mutations in the anaplastic lymphoma kinase (

    Topics: Aminopyridines; Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Genes, ras; Heterografts; Humans; Indoles; Male; MAP Kinase Signaling System; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasm Recurrence, Local; Neuroblastoma; Piperidines; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyridones; Pyrimidines; Pyrimidinones; Pyrroles; Triazoles; Vemurafenib

2020
Dress syndrome secondary to different combinations of targeted therapy (iBRAF + iMEK).
    European journal of dermatology : EJD, 2020, Jun-01, Volume: 30, Issue:3

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Hypersensitivity Syndrome; Female; Humans; Imidazoles; Melanoma; Neoplasms, Multiple Primary; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

2020
TTF-1 positive posterior pituitary tumor: Limitations of current treatment and potential new hope in BRAF V600E mutation variants.
    Clinical neurology and neurosurgery, 2020, Volume: 196

    Topics: Adenoma, Oxyphilic; Antineoplastic Agents; Humans; Imidazoles; Male; Middle Aged; Molecular Targeted Therapy; Mutation; Oximes; Pituitary Neoplasms; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Nuclear Factor 1

2020
Interim analysis for post-marketing surveillance of dabrafenib and trametinib combination therapy in Japanese patients with unresectable and metastatic melanoma with BRAF V600 mutation.
    International journal of clinical oncology, 2020, Volume: 25, Issue:10

    To investigate the safety and efficacy of dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive unresectable and metastatic melanoma in over 100 Japanese patients of a real-world clinical setting.. The surveillance period of interim post-marketing surveillance (PMS) analysis was from June 2016 to November 2018, and 112 patients with unresectable and metastatic BRAF V600 melanoma who received dabrafenib and trametinib were enrolled.. The safety analysis set included 112 patients whom almost all patients had stage IV disease (n = 97, 86.61%) with an Eastern Cooperative Oncology Group performance status 0 or 1 (n = 102, 91.07%), and mean (standard deviation) lactate dehydrogenase level was 354.3 (456.4) U/L (n = 105) at baseline. Median daily dose of dabrafenib was 300.0 mg/day (118-300), and median daily dose of trametinib was 2.00 mg/day (1.0-4.0). Adverse drug reactions (ADRs) were reported in 84 patients (75%), and common ADRs (incidence ≥ 5%) were pyrexia (n = 49, 43.75%), hepatic function abnormal (n = 11, 9.82%), rash and blood creatine phosphokinase increased (n = 9 each, 8.04%), and erythema nodosum (n = 6, 5.36%). Majority of ADRs reported in this study were consistent with that reported in previous trials. In the efficacy analysis set of 110 patients, the objective response rate was 55.45% (95% confidence interval 45.67-64.93%), and median progression-free survival was 384.0 days (251.0 days-not reached).. No new safety or efficacy concerns were observed in this interim PMS analysis in Japanese patients with unresectable and metastatic melanoma with BRAF gene mutation who received dabrafenib and trametinib combination therapy.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asian People; Female; Fever; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mutation; Oximes; Pregnancy; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Surveys and Questionnaires; Treatment Outcome; Young Adult

2020
Dextran methacrylate hydrogel microneedles loaded with doxorubicin and trametinib for continuous transdermal administration of melanoma.
    Carbohydrate polymers, 2020, Oct-15, Volume: 246

    Microneedles (MNs) technology has many advantages and is an ideal local transdermal drug delivery method. Here we synthesized photocrosslinkable dextran methacrylate (DexMA), and its degree of substitution is 5 % higher than the previous method. We used DexMA hydrogel for the first time to develop a new type of MNs for continuous transdermal administration. The prepared hydrogel MNs can successfully penetrate the epidermal layer and achieve sustained drug release. Doxorubicin (DOX) and trametinib (Tra) are anticancer drugs approved by FDA. Besides, Tra can also reverse P-gp-mediated multidrug resistance (MDR) to effectively block the efflux of DOX by P-gp. We used MNs to simultaneously load Tra and DOX, and achieved synergy in a B16 cell xenograft nude mouse model. The DexMA hydrogel MNs developed in this study can be used to enhance the transdermal delivery of small molecule drugs and reduce systemic toxicity and side effects.

    Topics: Administration, Cutaneous; Animals; Antineoplastic Agents; Cell Line, Tumor; Dextrans; Doxorubicin; Drug Delivery Systems; Drug Liberation; Drug Resistance, Neoplasm; Hydrogels; Melanoma, Experimental; Methacrylates; Mice; Mice, Nude; Neoplasm Transplantation; Permeability; Pyridones; Pyrimidinones; Skin; Skin Neoplasms; Tumor Burden

2020
Immunogenic chemotherapy effectively inhibits KRAS-Driven lung cancer.
    Cancer letters, 2020, 11-01, Volume: 492

    Immunogenic chemotherapy has been shown to be effective against several cancer types. Here, we identified trametinib as an inducer of immunogenic cell death (ICD), and found that it exerts beneficial antitumor effects if used in combination with interleukin (IL)-12 in a Kras-mutant mouse model of spontaneous lung cancer. Tumor cells treated with trametinib showed the hallmarks of ICD, including cell-surface expression of calreticulin, release of high mobility group box 1 (HMGB1) from the nucleus, and activation of dendritic cells. Tumor-bearing mice treated with both trametinib and IL-12 showed increased infiltration and proliferation of T cells within the tumor, as well as increased effector function of NK cells and T cells, indicating that this therapeutic combination can improve the quality of the immune response. Taken together, our results provide a potential new therapeutic regimen for the treatment of KRAS-mutant lung adenocarcinomas.

    Topics: Animals; Cell Line, Tumor; Interleukin-12; Lung Neoplasms; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mutation; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; T-Lymphocytes

2020
Trametinib for the treatment of recurrent/progressive pediatric low-grade glioma.
    Journal of neuro-oncology, 2020, Volume: 149, Issue:2

    Pediatric low-grade gliomas (pLGGs) are the most common CNS tumor of childhood and comprise a heterogenous group of tumors. Children with progressive pLGG often require numerous treatment modalities including surgery, chemotherapy, rarely radiation therapy and, more recently, molecularly targeted therapy. We describe our institutional experience using the MEK inhibitor, trametinib, for recurrent/progressive pLGGs.. We performed a retrospective, IRB-approved, chart review of all pediatric patients treated with trametinib for recurrent/progressive pLGGs at Dana-Farber/Boston Children's Cancer and Blood Disorder Center between 2016 and 2018.. Eleven patients were identified, of which 10 were evaluable for response. Median age at commencement of trametinib treatment was 14.7 years (range 7.3-25.9 years). Tumor molecular status included KIAA1549-BRAF fusion (n = 4), NF1 mutation (n = 4), FGFR mutation (n = 1) and CDKN2A loss (n = 1). Median number of prior treatment regimens was 5 (range 1-12). Median duration of treatment with trametinib was 19.2 months (range 3.8-29.8 months). Based on modified RANO criteria, best responses included partial (n = 2), minor response (n = 2) and stable disease (n = 6). Two patients remain on therapy (29.8 and 25.9 months, respectively). The most common toxicities attributable to trametinib were rash, fatigue and gastrointestinal disturbance. Five patients required dose reduction for toxicities. Two patients experienced significant intracranial hemorrhage (ICH) while on trametinib. While it is unclear whether ICH was directly attributable to trametinib, therapy was discontinued.. Trametinib appears to be an effective treatment for patients with recurrent/progressive pLGG. The toxicities of this therapy warrant further investigation, with particular attention to the potential risk for intracranial hemorrhage. Early phase multi-institutional clinical trials are underway.

    Topics: Adolescent; Adult; Antineoplastic Agents; Brain Neoplasms; Child; Female; Follow-Up Studies; Glioma; Humans; Male; Neoplasm Recurrence, Local; Prognosis; Pyridones; Pyrimidinones; Retrospective Studies; Young Adult

2020
Hemophagocytic lymphohistiocytosis in advanced melanoma treated with dabrafenib and trametinib combination: two cases.
    Melanoma research, 2020, Volume: 30, Issue:5

    Hemophagocytic lymphohistiocytosis (HLH) has been only rarely reported in patients with BRAF-mutated advanced melanoma treated with targeted therapies and never with first-line dabrafenib/trametinib combination thus far. Two patients treated with first-line dabrafenib and trametinib combination therapy for metastatic melanoma presented with sudden occurrence of fever, cytopenia, rhabdomyolysis, hepatic cytolysis, hypertriglyceridemia and very high ferritin levels after few weeks of treatment, associated with concomitant epstein-barr virus (EBV) reactivation in one patient. In both cases, drug-induced HLH was primarily considered owing to a high H-score and the absence of other etiology. Patients rapidly improved after treatment discontinuation associated with oral steroids in one patient and did not relapse after subsequent treatment resumption with a concurrent anti-BRAF/anti-MEK combination. In metastatic melanoma HLH may occur either spontaneously in the absence of any treatment as a paraneoplastic condition, related to an intercurrent infection or drug-induced mainly with various immunotherapy or with dabrafenib and trametinib following immunotherapy. However, such observations are scarce and these are the first cases of HLH occurring during first-line treatment with dabrafenib and trametinib in advanced melanoma to our knowledge. Pathomechanisms remain to be elucidated since triggering factors may encompass the treatment itself but also other significant actors including viral reactivation along with the underlying disease. The liability of treatment should be considered in cases of HLH occurring in patients with advanced melanoma successfully treated with a combined targeted therapy. A rechallenge with a concurrent anti-BRAF/anti-MEK can be proposed in this setting.

    Topics: Aged; Humans; Imidazoles; Lymphohistiocytosis, Hemophagocytic; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

2020
Multiplexed single-cell transcriptional response profiling to define cancer vulnerabilities and therapeutic mechanism of action.
    Nature communications, 2020, 08-27, Volume: 11, Issue:1

    Assays to study cancer cell responses to pharmacologic or genetic perturbations are typically restricted to using simple phenotypic readouts such as proliferation rate. Information-rich assays, such as gene-expression profiling, have generally not permitted efficient profiling of a given perturbation across multiple cellular contexts. Here, we develop MIX-Seq, a method for multiplexed transcriptional profiling of post-perturbation responses across a mixture of samples with single-cell resolution, using SNP-based computational demultiplexing of single-cell RNA-sequencing data. We show that MIX-Seq can be used to profile responses to chemical or genetic perturbations across pools of 100 or more cancer cell lines. We combine it with Cell Hashing to further multiplex additional experimental conditions, such as post-treatment time points or drug doses. Analyzing the high-content readout of scRNA-seq reveals both shared and context-specific transcriptional response components that can identify drug mechanism of action and enable prediction of long-term cell viability from short-term transcriptional responses to treatment.

    Topics: Antineoplastic Agents; Base Sequence; Cell Line, Tumor; Cell Survival; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Models, Statistical; Neoplasms; Polymorphism, Single Nucleotide; Pyridones; Pyrimidinones; Single-Cell Analysis

2020
Monitoring Arteriovenous Malformation Response to Genotype-Targeted Therapy.
    Pediatrics, 2020, Volume: 146, Issue:3

    Arteriovenous malformations (AVMs) have recently been reported to have a high incidence of somatic KRAS mutations suggesting potential for treatment with mitogen-activated protein kinase inhibitors. In this case report, we describe genotype-targeted treatment of a KRAS mutant metameric AVM in a patient with Cobb syndrome using the mitogen-activated protein kinase inhibitor trametinib. Therapeutic response was monitored with phase-contrast magnetic resonance angiography to quantify AVM arterial inflow as an imaging biomarker. Treatment with trametinib resulted in a substantial decrease in blood flow to the AVM, with a >75% reduction in arterial inflow after 6 months of trametinib therapy.

    Topics: Adolescent; Amino Acid Sequence; Arteriovenous Malformations; Drug Delivery Systems; Genotype; Humans; Male; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Spinal Cord Diseases; Syndrome; Treatment Outcome

2020
[Panniculitis in association with target therapy in melanoma patient, what the dermatologist should know: A case report].
    Medwave, 2020, Aug-26, Volume: 20, Issue:7

    Topics: Antineoplastic Combined Chemotherapy Protocols; Dermatologists; Humans; Imidazoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Oximes; Panniculitis; Pyridones; Pyrimidinones; Skin Neoplasms

2020
Loss of skeletal muscle area and fat-free mass during dabrafenib/trametinib and vemurafenib/cobimetinib treatments in patients with BRAF-mutant metastatic malignant melanoma.
    Melanoma research, 2020, Volume: 30, Issue:5

    This study aimed to assess whether dabrafenib/trametinib and vemurafenib/cobimetinib treatments are associated with a change in skeletal muscle area (SMA) and total fat-free mass (FFM) assessed by computed tomography (CT), and to compare the efficacy and safety profile of these treatments in patients with metastatic melanoma. Thirty-one patients treated with B-Raf proto-oncogene, serine/threonine kinase/MAPK extracellular receptor kinase inhibitors were included between 2016 and 2019. Eighteen patients received dabrafenib/trametinib and remaining patients received vemurafenib/cobimetinib. CT scans were performed at baseline and at 4-6 months of follow-up to measure cross-sectional areas of SMA. FFM and skeletal muscle index (SMI) values were calculated. Of the patients, including 18 treated with dabrafenib/trametinib (58.1%) and 13 with vemurafenib/cobimetinib (41.9%); 58.1% were male, 41.9% were female and median age was 52 years. A significant decrease in SMA was observed after dabrafenib/trametinib and vemurafenib/cobimetinib treatments (P = 0.003 and P = 0.002, respectively). A significant decrease in FFM values was observed after dabrafenib/trametinib and vemurafenib/cobimetinib treatments (P = 0.003 and P = 0.002, respectively). Dose-limiting toxicity (DLT) was observed in 35.9% of the patients with sarcopenia. No significant difference was seen between the dabrafenib/trametinib and vemurafenib/cobimetinib groups in median progression-free survival (PFS) (11.9 vs. 7.3 months, respectively, P = 0.28) and in median overall survival (OS) (25.46 vs. 13.7 months, respectively, P = 0.41). Baseline sarcopenia was not significantly associated with PFS or OS (P = 0.172 and P = 0.326, respectively). We found a significant decrease in SMI values determined at 4-6 months compared to the values before treatment both in dabrafenib/trametinib and vemurafenib/cobimetinib groups. DLT was similar with both treatments. Baseline sarcopenia was not significantly associated with PFS or OS.

    Topics: Azetidines; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

2020
Low‑dose trametinib and Bcl‑xL antagonist have a specific antitumor effect in KRAS‑mutated colorectal cancer cells.
    International journal of oncology, 2020, Volume: 57, Issue:5

    KRAS‑mutant colorectal cancer (CRC) is a highly malignant cancer with a poor prognosis, however specific therapies targeting KRAS mutations do not yet exist. Anti‑epidermal growth factor receptor (EGFR) agents, including cetuximab and panitumumab, are effective for the treatment of certain patients with CRC. However, these anti‑EGFR treatments have no effect on KRAS‑mutant CRC. Therefore, new therapeutic strategies targeting KRAS‑mutant CRC are urgently needed. To clarify the direct effect of KRAS gene mutations, the present study transduced mutant forms of the KRAS gene (G12D, G12V and G13D) into CACO‑2 cells. A drug‑screening system (Mix Culture assay) was then applied, revealing that the cells were most sensitive to the MEK inhibitor trametinib among tested drugs, Cetuximab, Panitumumab, Regorafenib, Vemurafenib, BEZ‑235 and Palbociclib. Trametinib suppressed phosphorylated ERK (p‑ERK) expression and inhibited the proliferation of KRAS‑mutant CACO‑2 cells. However, low‑dose treatment with trametinib also increased the expression of the anti‑apoptotic protein Bcl‑xL in a dose‑dependent manner, leading to drug resistance. To overcome the resistance of KRAS‑mutant CRC to apoptosis, the combination of trametinib and the Bcl‑xL antagonist ABT263 was assessed by in vitro and in vivo experiments. Compared with the effects of low‑dose trametinib monotherapy, combination treatment with ABT263 had a synergistic effect on apoptosis in mutant KRAS transductants in vitro. Furthermore, in vivo combination therapy using low‑dose trametinib and ABT263 against a KRAS‑mutant (G12V) xenograft synergistically suppressed growth, with an increase in apoptosis compared with the effects of trametinib monotherapy. These data suggest that a low dose of trametinib (10 nM), rather than the usual dose of 100 nM, in combination with ABT263 can overcome the resistance to apoptosis induced by Bcl‑xL expression, which occurs concurrently with p‑ERK suppression in KRAS‑mutant cells. This strategy may represent a promising new approach for treating KRAS‑mutant CRC.

    Topics: Aniline Compounds; Animals; Apoptosis; bcl-X Protein; Caco-2 Cells; Cell Proliferation; Colorectal Neoplasms; Extracellular Signal-Regulated MAP Kinases; Humans; Male; Mice; Mice, Inbred BALB C; Mutation; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Sulfonamides

2020
Structural basis for the action of the drug trametinib at KSR-bound MEK.
    Nature, 2020, Volume: 588, Issue:7838

    The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology

    Topics: Amino Acid Sequence; Animals; Binding Sites; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Models, Molecular; Protein Binding; Protein Kinase Inhibitors; Protein Kinases; Pyridones; Pyrimidinones; raf Kinases; Substrate Specificity

2020
Neuropsychological impact of trametinib in pediatric low-grade glioma: A case series.
    Pediatric blood & cancer, 2020, Volume: 67, Issue:12

    Clinical trials of MEK inhibitors are underway in pediatric low-grade glioma (PLGG) with BRAF oncogene mutations and recurrent/refractory disease. Cognitive and behavioral impacts of MEK inhibitors, such as trametinib, are unknown as these outcomes have not yet been studied. This case series compared cognition and behavior in eight PLGG cases prior to and while on treatment with trametinib compared to four PLGG controls. Intelligence in the trametinib cases was mainly unchanged while on treatment, with mild decline in one of seven cases with complete data. Parent-reported depression symptoms increased in five of eight trametinib cases relative to one of four controls.

    Topics: Antineoplastic Agents; Brain Neoplasms; Child; Child, Preschool; Cognitive Dysfunction; Depression; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Glioma; Humans; Infant; Male; Neuropsychological Tests; Prognosis; Pyridones; Pyrimidinones

2020
Chloroquine Sensitizes
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 12-01, Volume: 26, Issue:23

    Mutational activation of. These results suggest that YAP, MEK1/2, and lysosome function are necessary and critical targets for the therapy of GNAQ/11-driven melanoma, and identify trametinib plus hydroxychloroquine as a potential treatment strategy for metastatic uveal melanoma.

    Topics: Animals; Antimalarials; Apoptosis; Cell Proliferation; Chloroquine; Drug Resistance, Neoplasm; Drug Therapy, Combination; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Tumor Cells, Cultured; Uveal Neoplasms; Xenograft Model Antitumor Assays

2020
Repeated complete response with long-term control of BRAF-mutant melanoma by multiple rechallenges with dabrafenib plus trametinib.
    European journal of cancer (Oxford, England : 1990), 2020, Volume: 139

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2020
Functional imaging of RAS pathway targeting in malignant peripheral nerve sheath tumor cells and xenografts.
    Pediatric blood & cancer, 2020, Volume: 67, Issue:12

    Malignant peripheral nerve sheath tumor (MPNST) is an aggressive form of soft-tissue sarcoma (STS) in children. Despite intensive therapy, relatively few children with metastatic and unresectable disease survive beyond three years. RAS pathway activation is common in MPNST, suggesting MEK pathway inhibition as a targeted therapy, but the impact on clinical outcome has been small to date.. The ability of MEK inhibitors to control MPNST growth cannot simply be predicted by serum drug levels or drug-induced changes in pERK expression. Tumor cell proliferation assessed by

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Cell Proliferation; Fluorodeoxyglucose F18; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Neurofibrosarcoma; Positron Emission Tomography Computed Tomography; Pyridones; Pyrimidinones; Radiopharmaceuticals; ras Proteins; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2020
Durable Response to Dabrafenib Combined With Trametinib in a Patient With NSCLC Harboring a BRAF G469A Mutation.
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2020, Volume: 15, Issue:10

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2020
Langerhans cell histiocytosis with BRAF p.N486_P490del or MAP2K1 p.K57_G61del treated by the MEK inhibitor trametinib.
    Pediatric blood & cancer, 2020, Volume: 67, Issue:12

    Activating variants of the MAPK pathway have been found in some Langerhans cell histiocytosis (LCH) lesions. Inhibition of the MAPK pathway with trametinib (MEK inhibitor) has been shown to induce responses in LCH patients. Two adolescent males with LCH driven by BRAF p.N486_P490del have received trametinib for >1 year with no reactivation in one and partial response in another (including stable lung disease). A third male with neonatal LCH and MAP2K1p.K57_G61del had a complete response to trametinib with no active disease after 22 months. All patients continue on trametinib monotherapy with tolerable skin and creatine phosphokinase toxicity.

    Topics: Adolescent; Adult; Antineoplastic Agents; Gene Deletion; Histiocytosis, Langerhans-Cell; Humans; Male; MAP Kinase Kinase 1; Mutation; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Young Adult

2020
Response to trametinib treatment in progressive pediatric low-grade glioma patients.
    Journal of neuro-oncology, 2020, Volume: 149, Issue:3

    A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy.. In this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity.. We observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2-4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%).. Trametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens.

    Topics: Antineoplastic Agents; Child; Child, Preschool; Female; Follow-Up Studies; Glioma; Humans; Infant; Male; Prognosis; Pyridones; Pyrimidinones; Retrospective Studies

2020
Combined Inhibition of SHP2 and MEK Is Effective in Models of NF1-Deficient Malignant Peripheral Nerve Sheath Tumors.
    Cancer research, 2020, 12-01, Volume: 80, Issue:23

    Loss of the RAS GTPase-activating protein (RAS-GAP) NF1 drives aberrant activation of RAS/MEK/ERK signaling and other effector pathways in the majority of malignant peripheral nerve sheath tumors (MPNST). These dysregulated pathways represent potential targets for therapeutic intervention. However, studies of novel single agents including MEK inhibitors (MEKi) have demonstrated limited efficacy both preclinically and clinically, with little advancement in overall patient survival. By interrogation of kinome activity through an unbiased screen and targeted evaluation of the signaling response to MEK inhibition, we have identified global activation of upstream receptor tyrosine kinases (RTK) that converges on activation of RAS as a mechanism to limit sensitivity to MEK inhibition. As no direct inhibitors of pan-RAS were available, an inhibitor of the protein tyrosine phosphatase SHP2, a critical mediator of RAS signal transduction downstream of multiple RTK, represented an alternate strategy. The combination of MEKi plus SHP099 was superior to MEKi alone in models of NF1-MPNST, including those with acquired resistance to MEKi. Our findings have immediate translational implications and may inform future clinical trials for patients with MPNST harboring alterations in

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Nerve Sheath Neoplasms; Neurofibroma; Neurofibromin 1; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Pyridones; Pyrimidinones; ras Proteins; Small Molecule Libraries; Xenograft Model Antitumor Assays

2020
Physapubescin B enhances the sensitivity of gastric cancer cells to trametinib by inhibiting the STAT3 signaling pathway.
    Toxicology and applied pharmacology, 2020, 12-01, Volume: 408

    Given the poor prognosis of unresectable advanced gastric cancer (GC), novel therapeutic strategies are needed. The mitogen-activated protein kinase (MAPK) signaling cascade, the most frequently activated pathway in GC, plays an important role in tumorigenesis and metastasis. The MAPK/extracellular signal-regulated kinase (ERK) pathway is an attractive therapeutic target for GC. In this study, trametinib, a mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor, reduced the p-ERK level and significantly increased signal transducer and activator of transcription 3 (STAT3) phosphorylation in GC cells, resulting in reduced sensitivity to trametinib. Physapubescin B (PB), a steroidal compound extracted from the plant Physalis pubescens L., inhibited the proliferation and induced the apoptosis of GC cells by suppressing STAT3 phosphorylation. The combination of PB and trametinib suppressed the STAT3 phosphorylation induced by trametinib, and synergistically suppressed gastric tumor growth in vitro and in vivo. Together, these results indicate that inhibition of both MEK and STAT3 may be effective for patients with MAPK/ERK pathway-addicted GC.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Humans; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; STAT3 Transcription Factor; Stomach Neoplasms; Withanolides

2020
A highly sensitive and specific real-time quantitative PCR for BRAF V600E/K mutation screening.
    Scientific reports, 2020, 10-09, Volume: 10, Issue:1

    Mutations that lead to constitutive activation of key regulators in cellular processes are one of the most important drivers behind vigorous growth of cancer cells, and are thus prime targets in cancer treatment. BRAF V600E mutation transduces strong growth and survival signals for cancer cells, and is widely present in various types of cancers including lung cancer. A combination of BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) has recently been approved and significantly improved the survival of patients with advanced NSCLC harboring BRAF V600E/K mutation. To improve the detection of BRAF V600E/K mutation and investigate the incidence and clinicopathological features of the mutation in lung cancer patients of southern Taiwan, a highly sensitive and specific real-time quantitative PCR (RT-qPCR) method, able to detect single-digit copies of mutant DNA, was established and compared with BRAF V600E-specific immunohistochemistry. Results showed that the BRAF V600E mutation was present at low frequency (0.65%, 2/306) in the studied patient group, and the detection sensitivity and specificity of the new RT-qPCR and V600E-specific immunohistochemistry both reached 100% and 97.6%, respectively. Screening the BRAF V600E/K mutation with the RT-qPCR and V600E-specific immunohistochemistry simultaneously could help improve detection accuracy.

    Topics: Aged; Carcinoma, Non-Small-Cell Lung; Humans; Imidazoles; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Real-Time Polymerase Chain Reaction; Sensitivity and Specificity; Taiwan

2020
Complete response with combined BRAF and MEK inhibition in BRAF mutated advanced low-grade serous ovarian carcinoma.
    Upsala journal of medical sciences, 2020, Volume: 125, Issue:4

    More effective treatments are needed for low-grade serous ovarian carcinoma (LGSOC). Our patient, who suffers from metastatic LGSOC, had received all established treatments. Sequencing analysis revealed an activating BRAF mutation. Therefore, combined treatment with BRAF and MEK inhibitors, which is the gold standard in malignant melanoma, was initiated. After eight months of therapy, the response was assessed as complete and the treatment is still, 3.5 years after initiation, of benefit. To our knowledge, no complete response on combined BRAF and MEK inhibitor treatment of low-grade serous ovarian cancer has previously been reported.

    Topics: Antineoplastic Agents; Benzimidazoles; Bevacizumab; CA-125 Antigen; Carbamates; Carboplatin; Cystadenocarcinoma, Serous; Disease Progression; Everolimus; Female; High-Throughput Nucleotide Sequencing; Humans; Imidazoles; MAP Kinase Kinase 1; Medroxyprogesterone; Mutation; Neoplasm Metastasis; Neoplasm Recurrence, Local; Ovarian Neoplasms; Oximes; Paclitaxel; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Recurrence; Sulfonamides; Tamoxifen; Treatment Outcome; Young Adult

2020
Down-regulation of Aquaporin-1 mediates a microglial phenotype switch affecting glioma growth.
    Experimental cell research, 2020, 11-15, Volume: 396, Issue:2

    Aquaporin 1 (AQP1), a transmembrane protein that forms water channels, has previously been shown to facilitate growth and progression of many types of tumors by modulating tumor cell migration, proliferation and angiogenesis. Here, we determined the impact of AQP1 expression in the tumor environment on the progression of brain tumors. Primary microglia from wild type(WT) and AQP1 knockout(KO) mice were used to test AQP1 effect on microglia function by using Western blot, quantative PCR, in an experimental in vivo mouse glioma model and organotypic brain slice culture. Deletion of AQP1 in the host tissue significantly reduced the survival of the mice implanted with GL261 glioma cells. The density of glioma-associated microglia/macrophages was almost doubled in AQP1KO mice. We found that factors secreted from GL261 cells decrease microglial AQP1 expression via the MEK/ERK pathway, and that inhibition of this pathway with Trametinib reduced tumor growth and prolonged the survival of tumor bearing mice, an effect which required the presence of microglia. Deletion of AQP1 in cultured microglia resulted in an increase in migratory activity and a decrease in TLR4-dependent innate immune responses. Our study demonstrates a functional relevance of AQP1 expression in microglia and hints to AQP1 as a potential novel target for glioma therapy.

    Topics: Animals; Aquaporin 1; Astrocytes; Biomarkers, Tumor; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Down-Regulation; Gene Deletion; Gene Expression Regulation, Neoplastic; Glioma; Inflammation; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Phenotype; Pyridones; Pyrimidinones; RAW 264.7 Cells

2020
Erythema nodosum developed in a patient with advanced cutaneous melanoma treated with dabrafenib plus trametinib combination therapy.
    Dermatologic therapy, 2020, Volume: 33, Issue:6

    Topics: Antineoplastic Combined Chemotherapy Protocols; Erythema Nodosum; Humans; Imidazoles; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2020
Trametinib Induces the Stabilization of a Dual
    International journal of molecular sciences, 2020, Oct-28, Volume: 21, Issue:21

    We report a case of an uveal melanoma patient with

    Topics: Amino Acid Sequence; Antineoplastic Agents; Female; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Melanoma; Middle Aged; Models, Molecular; Mutant Proteins; Mutation; Protein Conformation; Protein Stability; Pyridones; Pyrimidinones; Receptor, Fibroblast Growth Factor, Type 4; Sequence Homology; Signal Transduction; Uveal Neoplasms

2020
Dabrafenib plus trametinib in patients with BRAF
    The Lancet. Oncology, 2020, Volume: 21, Issue:11

    Topics: Biliary Tract Neoplasms; Humans; Imidazoles; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2020
Dabrafenib plus trametinib in patients with BRAF
    The Lancet. Oncology, 2020, Volume: 21, Issue:11

    Topics: Biliary Tract Neoplasms; Humans; Imidazoles; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2020
Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma.
    Proceedings of the National Academy of Sciences of the United States of America, 2020, 12-01, Volume: 117, Issue:48

    Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, which limits surgical options and portends a dismal prognosis. Current oncologic PDAC therapies confer marginal benefit and, thus, a significant unmet clinical need exists for new therapeutic strategies. To identify effective PDAC therapies, we leveraged a syngeneic orthotopic PDAC transplant mouse model to perform a large-scale, in vivo screen of 16 single-agent and 41 two-drug targeted therapy combinations in mice. Among 57 drug conditions screened, combined inhibition of heat shock protein (Hsp)-90 and MEK was found to produce robust suppression of tumor growth, leading to an 80% increase in the survival of PDAC-bearing mice with no significant toxicity. Mechanistically, we observed that single-agent MEK inhibition led to compensatory activation of resistance pathways, including components of the PI3K/AKT/mTOR signaling axis, which was overcome with the addition of HSP90 inhibition. The combination of HSP90(i) + MEK(i) was also active in vitro in established human PDAC cell lines and in vivo in patient-derived organoid PDAC transplant models. These findings encourage the clinical development of HSP90(i) + MEK(i) combination therapy and highlight the power of clinically relevant in vivo model systems for identifying cancer therapies.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Benzodioxoles; Biomarkers, Tumor; Cell Line, Tumor; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Drug Synergism; Gene Expression; Humans; Immunohistochemistry; MAP Kinase Signaling System; Mice; Molecular Targeted Therapy; Pancreatic Neoplasms; Protein Kinase Inhibitors; Purines; Pyridones; Pyrimidinones; Signal Transduction; Survival Rate; Treatment Outcome; Xenograft Model Antitumor Assays

2020
Severe Lymphatic Disorder Resolved With MEK Inhibition in a Patient With Noonan Syndrome and SOS1 Mutation.
    Pediatrics, 2020, Volume: 146, Issue:6

    Noonan syndrome is a multiorgan system disorder mediated by genetic defects along the RASknown as RASopathies. It is the second most common syndromic cause of congenital heart disease and, in ∼20% of the cases, is associated with severe lymphatic disorders, including chylothorax and protein-losing enteropathy. Recently, we reported on the use of mitogen-activated protein kinase inhibition in a patient with an ARAF mutation and severe lymphatic disorder leading to an abrupt improvement in symptoms and complete remodeling of the central lymphatic system. Here, we present a patient with Noonan syndrome and severe lymphatic abnormality, leading to transfusion-dependent upper gastrointestinal bleeding and protein-losing enteropathy. The patient stopped responding to medical therapy and underwent several lymphatic interventional procedures, which led only to a temporary improvement in symptoms. Because of a lack of other treatment options, an expanded access approval was obtained, and the patient initiated treatment by mitogen-activated protein kinase inhibition using trametinib. This led to resolution of her symptoms, with complete normalization of her electrolyte levels, hemoglobin, and albumin within 3 months of starting the drug. Similar to the previously reported case, she also had complete and generalized remodeling of her lymphatic system. In patients with RAS pathway defects complicated by a severe lymphatic disorder, inhibition of the RAS-MAPK pathway should be considered as a possible treatment option in patients who failed conventional treatment and might be a first-line treatment in the future.

    Topics: DNA; DNA Mutational Analysis; Female; Humans; Infant, Newborn; Mitogen-Activated Protein Kinase Kinases; Mutation; Noonan Syndrome; Phenotype; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; SOS1 Protein

2020
Case Report: Immune-Related Toxicity During Adjuvant Treatment With BRAF Plus MEK Inhibitors in a Melanoma Patient.
    Frontiers in immunology, 2020, Volume: 11

    Adjuvant treatment of operated melanoma has deeply changed in the last few years with the introduction of immune-checkpoint inhibitors and BRAF/MEK inhibitors. Sarcoidosis is a systemic inflammatory disease causing non-caseous granulomatous reactions. Sarcoid-like granulomatous reactions have been reported in patients with advanced melanoma, mostly related to immunotherapy with immune-checkpoint inhibitors. We report a case of a 38-year-old woman with stage III operated melanoma treated with adjuvant BRAF plus MEK inhibitors, who developed sarcoidosis-like syndrome with systemic involvement, resolved after discontinuation of treatment. The occurrence of immune-related toxicity with the use of MAPK inhibitors supports the hypothesis that this class of drugs may also have an immunological effect, and that the long-term efficacy of adjuvant MAPK inhibitors may be due to their immunological function.

    Topics: Adrenal Cortex Hormones; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Imidazoles; MAP Kinase Kinase Kinases; Melanoma; Mutation; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sarcoidosis; Skin Neoplasms

2020
Trametinib and dabrafenib induced rhabdomyolysis, renal failure, and visual loss. Report of one case.
    Revista medica de Chile, 2020, Volume: 148, Issue:11

    MEK- and BRAF-inhibitors trametinib and dabrafenib are successfully used for BRAF-mutated, metastasizing melanoma, but these compounds may induce side effects. We report a 50 years old female with BRAF-mutated metastasizing melanoma who received trametinib (2 mg/d) and dabrafenib (200 mg/d) after using interferon without benefit. Shortly after starting trametinib/dabrafenib, she experienced an inability to abduct the left eye. Eight days after starting this therapy the patient experienced loss of appetite, vomiting, diarrhea, vertigo, and fever of 40°C. Two days later she experienced visual loss, requiring permanent support for her daily activities. Two further days later myoglobinuria appeared in the absence of myalgias or muscle weakness but accompanied by marked tiredness and inactivity. She could not eat or drink during four days prior to admission. The patient suspected an adverse effect of trametinib/dabrafenib and discontinued it 2 days prior to admission. Thereafter, she experienced an almost complete remission of the deficits except for ocular muscle weakness and visual impairment.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Renal Insufficiency; Rhabdomyolysis; Skin Neoplasms; Vision Disorders

2020
Trametinib Toxicities in Patients With Low-grade Gliomas and Diabetes Insipidus: Related Findings?
    Journal of pediatric hematology/oncology, 2020, Volume: 42, Issue:4

    Low-grade gliomas (LGG) represent the most common form of primary central nervous system tumor arising in childhood. There is growing evidence to support the role of the mitogen-activated protein kinase pathway in driving tumor growth and MEK inhibitors are being investigated in clinical trials for refractory and unresectable LGGs. As MEK inhibitors progress through clinical trials, drug toxicities have been identified. We report on 2 pediatric patients with LGG and known diabetes insipidus who developed severe hyponatraemia associated with significant decreases in desmopressin doses after starting trametinib. We review potential mechanisms for this sodium imbalance by examining the interaction between MEK inhibition and aquaporin channel physiology. We recommend close monitoring of serum sodium levels and clinical status in patients with diabetes insipidus who have optic-hypothalamic gliomas and are started on treatment with MEK inhibitors.

    Topics: Child; Diabetes Insipidus; Eye Neoplasms; Female; Glioma; Humans; Hypothalamic Neoplasms; Pyridones; Pyrimidinones

2020
Gut dysbiosis: not only with checkpoint inhibitors!
    Clinical and experimental dermatology, 2020, Volume: 45, Issue:2

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bacterial Translocation; Dysbiosis; Enterobacter cloacae; Fatal Outcome; Feces; Female; Gastrointestinal Microbiome; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones

2020
Disseminated metastatic cutaneous melanoma to pancreas and upper gastrointestinal tract diagnosed by endoscopic ultrasound: an unusual case.
    Clinical journal of gastroenterology, 2020, Volume: 13, Issue:1

    There is a wide variety of pancreatic neoplasms identified, but the great majority of them are of primary origin. Metastatic disease in the pancreatic parenchyma is quite rare (2-5% of pancreatic malignancies) and most often is quite difficult to differentiate from other primary lesions. Most of the imaging studies fail to give certain discriminating features for metastatic pancreatic neoplasms, contrary to endoscopic ultrasound and tissue sampling, which can provide an accurate diagnosis. In this report, we present a case of a male middle aged man who was admitted to our hospital with painless jaundice and finally was diagnosed with a cutaneous scalp melanoma dispersedly metastasized to the pancreas and upper gastrointestinal tract (stomach and duodenum).

    Topics: Adrenal Gland Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cholangiopancreatography, Endoscopic Retrograde; Cranial Irradiation; Duodenal Neoplasms; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Endoscopy, Digestive System; Endosonography; Humans; Imidazoles; Lung Neoplasms; Male; Melanoma; Middle Aged; Oximes; Pancreatic Neoplasms; Pyridones; Pyrimidinones; Skin Neoplasms; Stomach Neoplasms; Tomography, X-Ray Computed

2020
Neoadjuvant BRAF-targeted therapy in regionally advanced and oligometastatic melanoma.
    Pigment cell & melanoma research, 2020, Volume: 33, Issue:1

    Current management of locoregional and oligometastatic melanoma is typically with surgery; however, some patients are unable to undergo resection due to location/size of their tumors and/or the anticipated morbidity of the surgery. While there are currently no established guidelines for neoadjuvant therapy in melanoma, neoadjuvant BRAF-targeted therapy may make resection more feasible. A retrospective analysis was conducted of 23 patients with BRAFV600-mutant, stage III/IV melanoma treated with BRAF-targeted therapy prior to surgery, with no adjuvant treatment. Surgical specimens, preoperative imaging, and clinical outcomes were evaluated. Results: Ten of 23 patients (44%) attained a pathologic complete response (pCR), with no correlation between RECIST response based on preoperative imaging and pathologic response. After a median of 43-month follow-up, only 1 patient (10%) with a pCR recurred, while 8 of 13 (62%) patients without a pCR recurred. Patients with a pCR had significantly improved relapse-free (RFS) and overall survival (OS) compared to patients with residual tumor. Neoadjuvant BRAF-targeted therapy is associated with a high pCR rate in patients with stage III-IV melanoma, which may correlate with improved RFS and OS.

    Topics: Adult; Aged; Disease-Free Survival; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

2020
A pharmacogenomic analysis using L1000CDS
    Cancer letters, 2019, Nov-28, Volume: 465

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta; Humans; Inhibitory Concentration 50; Male; Mice; Pancreatic Neoplasms; Pharmacogenomic Testing; Pyridones; Pyrimidines; Pyrimidinones; Signal Transduction; Thiophenes; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

2019
Resistance to TRK inhibition mediated by convergent MAPK pathway activation.
    Nature medicine, 2019, Volume: 25, Issue:9

    TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition

    Topics: Adolescent; Adult; Animals; Benzamides; Cell Proliferation; Cell-Free Nucleic Acids; Child; Clinical Trials as Topic; Drug Resistance, Neoplasm; Female; Heterografts; Humans; Imidazoles; Indazoles; Male; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Neoplasms; Oncogene Proteins, Fusion; Oximes; Protein Kinase Inhibitors; Pyrazoles; Pyridones; Pyrimidines; Pyrimidinones; Receptor, trkA; Young Adult

2019
Autoimmune hemolytic anemia in refractory hairy cell leukemia on dabrafenib and trametinib.
    Annals of hematology, 2019, Volume: 98, Issue:10

    Topics: Aged; Anemia, Hemolytic, Autoimmune; Humans; Imidazoles; Leukemia, Hairy Cell; Male; Oximes; Pyridones; Pyrimidinones

2019
[BRAF-mutated metastatic melanoma: first results on long-term efficacy of targeted therapies].
    Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al], 2019, Volume: 195, Issue:10

    Topics: Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2019
Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: Effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202.
    Biochemical pharmacology, 2019, Volume: 169

    We have demonstrated previously that the kinase inhibitors (KIs) lapatinib, pazopanib, regorafenib and sorafenib are potent inhibitors of UGT1A1 and UGTs 1A7-1A10. The present study characterised the effects of four additional drugs in this class, dabrafenib, ibrutinib, nintedanib and trametinib, on human UGT enzyme activities in vitro. Dabrafenib, ibrutinib, nintedanib and trametinib were potent inhibitors of human liver microsomal UGT1A1; K

    Topics: Adenine; Glucuronosyltransferase; Humans; Imidazoles; Indoles; Microsomes, Liver; Oximes; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridones; Pyrimidines; Pyrimidinones

2019
Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors.
    International journal of molecular sciences, 2019, Aug-29, Volume: 20, Issue:17

    Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.

    Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cell Line, Tumor; Melanoma; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinases; Morpholines; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; Skin Neoplasms; Treatment Outcome; Tumor Burden; Xenograft Model Antitumor Assays

2019
Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer.
    Science translational medicine, 2019, 09-18, Volume: 11, Issue:510

    KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated protein kinase kinase (MEK) and insulin-like growth factor 1 receptor (IGF1R) signaling. Here, we show that this effect is markedly enhanced by simultaneous inhibition of mammalian target of rapamycin (mTOR) while maintaining selectivity for the KRAS-mutant genotype. Combined mTOR, IGF1R, and MEK inhibition inhibits the principal signaling pathways required for the survival of KRAS-mutant cells and produces marked tumor regression in three different KRAS-driven lung cancer mouse models. Replacing the MEK inhibitor with the mutant-specific KRAS-G12C inhibitor ARS-1620 in these combinations is associated with greater efficacy, specificity, and tolerability. Adding mTOR and IGF1R inhibitors to ARS-1620 greatly improves its effectiveness on KRAS-G12C mutant lung cancer cells in vitro and in mouse models. This provides a rationale for the design of combination treatments to enhance the impact of the KRAS-G12C inhibitors, which are now entering clinical trials.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Survival; Imidazoles; Lung Neoplasms; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Mutation; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); Pyrazines; Pyridones; Pyrimidinones; Receptor, IGF Type 1; RNA, Small Interfering; Signal Transduction; TOR Serine-Threonine Kinases

2019
Response to the Combination of Osimertinib and Trametinib in a Patient With EGFR-Mutant NSCLC Harboring an Acquired BRAF Fusion.
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2019, Volume: 14, Issue:10

    Topics: Acrylamides; Adenocarcinoma of Lung; Angiopoietin-Like Protein 6; Angiopoietin-like Proteins; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Neoplasm Metastasis; Oncogene Proteins, Fusion; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2019
Acquired BRAF V600E Mutation Mediated Resistance to Osimertinib and Responded to Osimertinib, Dabrafenib, and Trametinib Combination Therapy.
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2019, Volume: 14, Issue:10

    Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2019
BRAF exon 11 mutant melanoma and sensitivity to BRAF/MEK inhibition: Two case reports.
    European journal of cancer (Oxford, England : 1990), 2019, Volume: 121

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Exons; Female; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2019
A triple drug combination targeting components of the nutrient-sensing network maximizes longevity.
    Proceedings of the National Academy of Sciences of the United States of America, 2019, 10-15, Volume: 116, Issue:42

    Increasing life expectancy is causing the prevalence of age-related diseases to rise, and there is an urgent need for new strategies to improve health at older ages. Reduced activity of insulin/insulin-like growth factor signaling (IIS) and mechanistic target of rapamycin (mTOR) nutrient-sensing signaling network can extend lifespan and improve health during aging in diverse organisms. However, the extensive feedback in this network and adverse side effects of inhibition imply that simultaneous targeting of specific effectors in the network may most effectively combat the effects of aging. We show that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, the mTOR complex 1 (mTORC1) inhibitor rapamycin, and the glycogen synthase kinase-3 (GSK-3) inhibitor lithium act additively to increase longevity in

    Topics: Aged; Aging; Animals; Drosophila; Drosophila Proteins; Drug Combinations; Female; Glycogen Synthase Kinase 3; Humans; Lithium; Longevity; Mechanistic Target of Rapamycin Complex 1; Middle Aged; Nutrients; Pyridones; Pyrimidinones; Signal Transduction; Sirolimus

2019
A flitting pneumonia in a patient with advanced melanoma.
    British journal of hospital medicine (London, England : 2005), 2019, Oct-02, Volume: 80, Issue:10

    Topics: Aged; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Drug Substitution; Drug Therapy, Combination; Dyspnea; Fever; Humans; Imidazoles; Male; Melanoma; Oximes; Pneumonia; Pyridones; Pyrimidinones; Skin Neoplasms

2019
Tumour response to TRK inhibition in a patient with pancreatic adenocarcinoma harbouring an NTRK gene fusion.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2019, 11-01, Volume: 30, Issue:Suppl_8

    Although rare, NTRK gene fusions are known to be oncogenic drivers in pancreatic ductal adenocarcinoma (PDAC). We report the response of a metastatic CTRC-NTRK1 gene fusion-positive PDAC to targeted treatment with the oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib and the eventual development of resistance to treatment.. A 61-year-old woman presented with a 2.5-cm mass in the body of the pancreas and a 1.2-cm liver lesion on routine follow-up for endometrial cancer that was in complete remission. Liver biopsy confirmed a primary PDAC unrelated to the endometrial cancer. The patient was treated with gemcitabine, nab-paclitaxel and ADI-PEG 20 for 12 months until disease progression and toxicity emerged [best overall response (BOR): partial response (PR)]. The patient switched to a modified regimen of folinic acid, fluorouracil, irinotecan and oxaliplatin for 4 months until neuropathy occurred. Oxaliplatin was withheld until disease progression 6 months later (BOR: stable disease). Despite recommencing oxaliplatin, the disease continued to progress. At this time, somatic profiling of the liver lesion revealed a CTRC-NTRK1 gene fusion. Treatment with larotrectinib 100 mg twice daily was commenced with BOR of PR at 2 months. The patient progressed after 6 months and was re-biopsied. Treatment was switched to the investigational next-generation TRK inhibitor selitrectinib (BAY 2731954, LOXO-195) 100 mg twice daily. After 2 months, the disease progressed and dabrafenibtrametinib combination therapy was initiated due to existence of a BRAF-V600E mutation. However, the cancer continued to progress and the patient died 2 months later.. Targeted TRK inhibition with larotrectinib in PDAC harbouring a CTRC-NTRK1 gene fusion is well tolerated and can improve quality of life for the patient. However, acquired resistance to therapy can emerge in some patients. Next-generation TRK inhibitors such as selitrectinib are currently in development to overcome this resistance (NCT02576431; NCT03215511).

    Topics: Antineoplastic Combined Chemotherapy Protocols; Aza Compounds; Carcinoma, Pancreatic Ductal; Chymotrypsin; Female; Humans; Imidazoles; Middle Aged; Oncogene Proteins, Fusion; Oximes; Pancreatic Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Pyrazoles; Pyridones; Pyrimidines; Pyrimidinones; Receptor, trkA

2019
[Tattoo hypersensitivity reaction in a patient receiving combined BRAF and MEK inhibitors].
    Annales de dermatologie et de venereologie, 2019, Volume: 146, Issue:11

    For inflammation of a tattoo occurring decades after its creation, sarcoidosis should be considered first of all. Two case of extremely delayed hypersensitivity tattoo reaction have been recently reported in patients treated with BRAF and MEK inhibitors. We report a similar new case strongly suggesting a specific effect of this drug combination.. A 58-year-old man bearing 20-year-old tattoos was treated with dabrafenib and trametinib for advanced melanoma. A painful erythematous swelling appeared on all the patient's tattoos two months later, while his general tolerance of the treatment was poor. Skin biopsy demonstrated perivascular lympho-histiocytic infiltrate without granuloma, but with prominent pigment-loaded macrophages. Inflammatory signs quickly regressed after drug discontinuation.. Great similarity exists between this new case and the first reported case, in which a female patient presented painful infiltration of old tattoos following repeated reintroduction of dabrafenib and trametinib in a setting of advanced melanoma. The immunomodulatory properties BRAF/MEK inhibition may enhance loss of tolerance to tattoo ink, accounting for the extremely long time to reaction. This third case militates in favour of a specific drug-induced reaction, of which patients with tattoos should be informed when anti-BRAF/MEK therapy is being considered.

    Topics: Erythema; Humans; Hypersensitivity; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Tattooing

2019
Integrative Exome and Transcriptome Analysis of Conjunctival Melanoma and Its Potential Application for Personalized Therapy.
    JAMA ophthalmology, 2019, 12-01, Volume: 137, Issue:12

    Greater understanding of molecular features of conjunctival melanoma (CM) may improve its clinical management.. To evaluate molecular features of CM and application of this information into clinical care.. In a prospective case series of CM with integrative exome and transcriptome analysis, 8 patients at an academic ocular oncology setting were evaluated. The study was conducted from November 2015 to March 2018.. Integrative exome and transcriptome analysis of CMs and clinical management of a patient's care by using this information.. Molecular characterization of CM and its potential clinical application.. In the 8 patients (4 men) included in analysis, 4 subgroups of CM were observed, including the BRAF V600E mutation in 1 tumor, NRAS Q61R mutation in 3 tumors, NF1 mutations (Q1188X, R440X, or M1215K+ S15fs) in 3 tumors, and triple-wild type (triple-WT) in 1 tumor. The triple-WT case had CCND1 amplification and mutation in the CIC gene (Q1508X). Five tumors, including the triple-WT, also harbored mutations in MAPK genes. In addition to the genes linked to mitogen-activated protein kinase and phosphoinositol 3-kinase pathways, those involved in cell cycle and/or survival, ubiquitin-mediated protein degradation, and chromatin remodeling/epigenetic regulation (ATRX being the most frequently mutated: noted in 5 tumors) may play an important role. Other frequently mutated genes included PREX2 (n = 3), APOB (n = 4), and RYR1/2 (n = 4), although their relevance remains to be determined. The mutation burden ranged from 1.1 to 15.6 mutations per megabase (Mut/Mb) and was 3.3 Mut/Mb or less in 3 tumors and more than 10 Mut/Mb in 2 tumors. A patient with a large tumor and BRAF V600E mutation was treated with combined systemic BRAF (dabrafenib) and MEK (trametinib) inhibitors. After 3 months of therapy, her CM responded substantially and the residual tumor was removed by local surgical excision.. The NRAS Q61R and NF1 mutations were more common than the BRAF V600E mutation in this series. Although small tumors (where incisional biopsy is not indicated) are treated with surgical excision regardless of mutational profile, in large tumors carrying the BRAF V600E mutation, neoadjuvant therapy with combined systemic BRAF and MEK inhibitors followed by local excision may be used as an alternative to exenteration. Integrative omics analysis of CM may be informative and guide clinical management and treatment in selected cases.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Conjunctival Neoplasms; DNA Mutational Analysis; Exome; Female; Gene Expression Profiling; GTP Phosphohydrolases; Humans; Imidazoles; Male; Melanoma; Membrane Proteins; Neurofibromin 1; Oximes; Precision Medicine; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2019
Budget Impact of Dabrafenib and Trametinib in Combination as Adjuvant Treatment of BRAF V600E/K Mutation-Positive Melanoma from a U.S. Commercial Payer Perspective.
    Journal of managed care & specialty pharmacy, 2019, Volume: 25, Issue:11

    Before the approval of dabrafenib and trametinib in combination, there were no approved therapies in the adjuvant setting that target the RAS/RAF/MEK/ERK pathway.. To evaluate the budget impact of dabrafenib and trametinib in combination for adjuvant treatment of patients with BRAF V600 mutation-positive resected Stage IIIA, IIIB, or IIIC melanoma from a U.S. commercial payer perspective using data from the COMBI-AD trial, as well as other sources.. The budget impact of dabrafenib and trametinib in combination for patients with BRAF V600E/K mutation-positive, resected Stage IIIA, IIIB, or IIIC melanoma was evaluated from the perspective of a hypothetical population of 1 million members with demographic characteristics consistent with those of a commercially insured U.S. insurance plan (i.e., adults aged less than 65 years) using an economic model developed in Microsoft Excel. The model compared melanoma-related health care costs over a 3-year projection period under 2 scenarios: (1) a reference scenario in which dabrafenib and trametinib are assumed to be unavailable for adjuvant therapy and (2) a new scenario in which the combination is assumed to be available. Treatments potentially displaced by dabrafenib and trametinib were assumed to include observation, high-dose interferon alpha-2b, ipilimumab, and nivolumab. Costs considered in the model include those of adjuvant therapies and treatment of locoregional and distant recurrences. The numbers of patients eligible for treatment with dabrafenib and trametinib were based on data from cancer registries, published sources, and assumptions. Treatment mixes under the reference and new scenarios were based on market research data, clinical expert opinion, and assumptions. Probabilities of recurrence and death were based on data from the COMBI-AD trial and an indirect treatment comparison. Medication costs were based on wholesale acquisition cost prices. Costs of distant recurrence were from a health insurance claims study.. In a hypothetical population of 1 million commercially insured members, 48 patients were estimated to become eligible for treatment with dabrafenib and trametinib in combination over the 3-year projection period; in the new scenario, 10 patients were projected to receive such treatment. Cumulative costs of melanoma-related care were estimated to be $6.3 million in the reference scenario and $6.9 million in the new scenario. The budget impact of dabrafenib and trametinib in combination was an increase of $549 thousand overall and 1.5 cents per member per month.. For a hypothetical U.S. commercial health plan of 1 million members, the budget impact of dabrafenib and trametinib in combination as adjuvant treatment for melanoma is likely to be relatively modest and within the range of published estimates for oncology therapies. These results may assist payers in making coverage decisions regarding the use of adjuvant dabrafenib and trametinib in melanoma.. Funding for this research was provided to Policy Analysis Inc. (PAI) by Novartis Pharmaceuticals. Stellato, Moynahan, and Delea are employed by PAI. Ndife, Koruth, Mishra, and Gunda are employed by Novartis. Ghate was employed by Novartis at the time of this study and is shareholder in Novartis, Provectus Biopharmaceuticals, and Mannkind Corporation. Gerbasi was employed by PAI at the time of this study and is currently an employee, and stockholder, of Sage Therapeutics. Delea reports grant funding from Merck and research funding from Amgen, Novartis, Sanofi, Seattle Genetics, Takeda, Jazz, EMD Serono, and 21st Century Oncology, unrelated to this work.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Budgets; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Decision Making; Disease-Free Survival; Drug Costs; For-Profit Insurance Plans; Humans; Imidazoles; Male; Melanoma; Middle Aged; Models, Economic; Mutation; Oximes; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2019
YAP1 Mediates Resistance to MEK1/2 Inhibition in Neuroblastomas with Hyperactivated RAS Signaling.
    Cancer research, 2019, 12-15, Volume: 79, Issue:24

    Topics: Adaptor Proteins, Signal Transducing; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Mutation; Neuroblastoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Transcription Factors; YAP-Signaling Proteins

2019
MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia.
    Scientific reports, 2019, 12-09, Volume: 9, Issue:1

    FMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several tyrosine kinase inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence of drug-resistance. Thus, a better understanding of drug-resistance pathways could be a good strategy to explore and evaluate new combinational therapies for AML. Here, we used phosphoproteomics to identify differentially-phosphorylated proteins in patients with AML and TKI resistance. We then studied resistance mechanisms in vitro and evaluated the efficacy and safety of rational combinational therapy in vitro, ex vivo and in vivo in mice. Proteomic and immunohistochemical studies showed the sustained activation of ERK1/2 in bone marrow samples of patients with AML after developing resistance to FLT3 inhibitors, which was identified as a common resistance pathway. We examined the concomitant inhibition of MEK-ERK1/2 and FLT3 as a strategy to overcome drug-resistance, finding that the MEK inhibitor trametinib remained potent in TKI-resistant cells and exerted strong synergy when combined with the TKI midostaurin in cells with mutated and wild-type FLT3. Importantly, this combination was not toxic to CD34+ cells from healthy donors, but produced survival improvements in vivo when compared with single therapy groups. Thus, our data point to trametinib plus midostaurin as a potentially beneficial therapy in patients with AML.

    Topics: Adult; Aged; Animals; Antigens, CD34; Bone Marrow Cells; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Female; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Male; MAP Kinase Kinase Kinase 1; MAP Kinase Signaling System; Mice; Middle Aged; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Staurosporine

2019
Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma.
    Acta pharmacologica Sinica, 2019, Volume: 40, Issue:2

    Topics: Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Imidazoles; MAP Kinase Signaling System; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Ribosomal Protein S6; TOR Serine-Threonine Kinases

2019
Acute encephalopathy secondary to dabrafenib and trametinib in BRAF-positive metastatic adenocarcinoma of the lung.
    Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 2019, Volume: 25, Issue:6

    Acute encephalopathy secondary to targeted therapy with BRAF inhibitors is uncommon. There are few case reports in patients with metastatic melanoma who received treatment with dabrafenib and trametinib, and developed acute confusion. The encephalopathy appears to resolve after the discontinuation of offending drug, with patient returning to their baseline mentation and functional ability. The mechanism of the encephalopathy has been unclear. Unlike posterior reversible encephalopathy syndrome, which has been reported with vemurafenib and cobimetinib combination in melanoma patients, there are generally no acute imaging abnormalities observed (e.g. on computed tomography and magnetic resonance imaging brain scans). We report a case of acute encephalopathy in a patient with BRAF mutated metastatic lung cancer due to dabrafenib and trametinib treatment. With the increasing use of targeted therapies in lung cancer treatments, it is important for clinicians to be aware of potentially toxic effects of novel treatments.

    Topics: Adenocarcinoma of Lung; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Humans; Imidazoles; Male; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2019
BRAF
    International journal of cancer, 2019, 03-15, Volume: 144, Issue:6

    To determine the role of BRAF

    Topics: Aged; Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Neuroendocrine; Cell Line, Tumor; Colorectal Neoplasms; Exons; Female; Follow-Up Studies; G1 Phase Cell Cycle Checkpoints; Humans; Imidazoles; Intestinal Neoplasms; Male; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Neuroendocrine Tumors; Oximes; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Stomach Neoplasms; Survival Analysis; Tissue Array Analysis; Vemurafenib; Xenograft Model Antitumor Assays

2019
BRAFi/MEKi in patients with metastatic melanoma: predictive factors of complete response.
    Future oncology (London, England), 2019, Volume: 15, Issue:2

    A survival benefit was demonstrated by dabrafenib + trametinib for metastatic BRAF-mutated melanoma patients. Best response is a strong prognostic marker for survival.. The specific features associated with complete response (CR) were evaluated.. A total of 15/66 patients achieved CR. Median size of lesions was 3 cm (range: 0.5-10). Using that value as cut-off, the CR rate was 39.3% in patients with smaller lesions and 10.5% in patients with bigger size (p = 0.006). The clinical features associated with CR were the number of metastatic sites and the largest diameter of the biggest metastatic site.. The number of the metastases and the diameter of the largest metastatic site are associated with a higher CR rate.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vemurafenib

2019
Dabrafenib plus trametinib in BRAF K601E-mutant melanoma.
    The British journal of dermatology, 2019, Volume: 180, Issue:2

    Topics: Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Male; Melanoma; Mice; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin; Skin Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

2019
Dramatic response to trametinib in a male child with neurofibromatosis type 1 and refractory astrocytoma.
    Pediatric blood & cancer, 2019, Volume: 66, Issue:1

    Topics: Antineoplastic Agents; Astrocytoma; Drug Resistance, Neoplasm; Humans; Infant; Male; Neurofibromatosis 1; Prognosis; Pyridones; Pyrimidinones; Remission Induction; Salvage Therapy

2019
Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction.
    Platelets, 2019, Volume: 30, Issue:6

    The MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but their role in platelet function and haemostasis is ambiguous as previous reports have been contradictory. It is therefore unclear if MEK inhibitors might be causing platelet dysfunction and contributing to increased hemorrhage. In the present study we performed pharmacological characterisation of cobimetinib and trametinib

    Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Blood Platelets; Humans; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2019
Anaplastic pleomorphic xanthoastrocytoma with leptomeningeal dissemination responsive to BRAF inhibition and bevacizumab.
    Pediatric blood & cancer, 2019, Volume: 66, Issue:1

    Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Bevacizumab; Brain Neoplasms; Female; Humans; Imidazoles; Meningeal Carcinomatosis; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2019
Targeting Resistance against the MDM2 Inhibitor RG7388 in Glioblastoma Cells by the MEK Inhibitor Trametinib.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 01-01, Volume: 25, Issue:1

    Resistance is an obstacle of glioma therapy. Despite targeted interventions, tumors harbor primary resistance or become resistant over short course of treatment. This study examined the mouse double minute 2 (MDM2) inhibitor RG7388 together with radiotherapy and analyzed strategies to overcome acquired MDM2 inhibitor resistance in glioblastoma.. Effects of RG7388 and radiotherapy were analyzed in p53 wild-type glioblastoma cell lines and glioma-initiating cells. RG7388 resistant cells were generated by increasing RG7388 doses over 3 months. Regulated pathways were investigated by microarray, qRT-PCR, and immunoblot analysis and specifically inhibited to evaluate rational salvage therapies at RG7388 resistance. Effects of RG7388 and trametinib treatment were challenged in an orthotopical mouse model with RG7388 resistant U87MG glioblastoma cells.. MDM2 inhibition required functional p53 and showed synergistic activity with radiotherapy in first-line treatment. Long-term exposure to RG7388 induced resistance by activation of the extracellular signal-regulated kinases 1/2 (ERK1/2)-insulin growth factor binding protein 1 (IGFBP1) signaling cascade, which was specifically overcome by ERK1/2 pathway inhibition with trametinib and knockdown of IGFBP1. Combining trametinib with continued RG7388 treatment enhanced antitumor effects at RG7388 resistance. These data provide a rationale for combining RG7388 and radiotherapy as first-line therapy with a specific relevance for tumors insensitive to alkylating standard chemotherapy and for the addition of trametinib to continued RG7388 treatment as salvage therapy after acquired resistance against RG7388 for clinical practice.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Resistance, Neoplasm; Glioblastoma; Heterografts; Humans; Insulin-Like Growth Factor Binding Protein 1; Mice; para-Aminobenzoates; Proto-Oncogene Proteins c-mdm2; Pyridones; Pyrimidinones; Pyrrolidines; Signal Transduction; Tumor Suppressor Protein p53

2019
Phosphoprotein patterns predict trametinib responsiveness and optimal trametinib sensitisation strategies in melanoma.
    Cell death and differentiation, 2019, Volume: 26, Issue:8

    Malignant melanoma is a highly aggressive form of skin cancer responsible for the majority of skin cancer-related deaths. Recent insight into the heterogeneous nature of melanoma suggests more personalised treatments may be necessary to overcome drug resistance and improve patient care. To this end, reliable molecular signatures that can accurately predict treatment responsiveness need to be identified. In this study, we applied multiplex phosphoproteomic profiling across a panel of 24 melanoma cell lines with different disease-relevant mutations, to predict responsiveness to MEK inhibitor trametinib. Supported by multivariate statistical analysis and multidimensional pattern recognition algorithms, the responsiveness of individual cell lines to trametinib could be predicted with high accuracy (83% correct predictions), independent of mutation status. We also successfully employed this approach to case specifically predict whether individual melanoma cell lines could be sensitised to trametinib. Our predictions identified that combining MEK inhibition with selective targeting of c-JUN and/or FAK, using siRNA-based depletion or pharmacological inhibitors, sensitised resistant cell lines and significantly enhanced treatment efficacy. Our study indicates that multiplex proteomic analyses coupled with pattern recognition approaches could assist in personalising trametinib-based treatment decisions in the future.

    Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Melanoma; Pyridones; Pyrimidinones

2019
Harnessing autophagy to overcome mitogen-activated protein kinase kinase inhibitor-induced resistance in metastatic melanoma.
    The British journal of dermatology, 2019, Volume: 180, Issue:2

    Patients with malignant melanoma often relapse after treatment with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors (MEKi) owing to development of drug resistance.. To establish the temporal pattern of CD271 regulation during development of resistance by melanoma to trametinib, and determine the association between development of resistance to trametinib and induction of prosurvival autophagy.. Immunohistochemistry for CD271 and p62 was performed on human naevi and primary malignant melanoma tumours. Western blotting was used to analyse expression of CD271, p62 and LC3 in melanoma subpopulations. Flow cytometry and immunofluorescence microscopy was used to evaluate trametinib-induced cell death and CD271 expression. MTS viability assays and zebrafish xenografts were used to evaluate the effect of CD271 and autophagy modulation on trametinib-resistant melanoma cell survival and invasion, respectively.. CD271 and autophagic signalling are increased in stage III primary melanomas vs. benign naevi. In vitro studies demonstrate MEKi of BRAF-mutant melanoma induced cytotoxic autophagy, followed by the emergence of CD271-expressing subpopulations. Trametinib-induced CD271 reduced autophagic flux, leading to activation of prosurvival autophagy and development of MEKi resistance. Treatment of CD271-expressing melanoma subpopulations with RNA interference and small-molecule inhibitors to CD271 reduced the development of MEKi resistance, while clinically applicable autophagy modulatory agents - including Δ9-tetrahydrocannabinol and Vps34 - reduced survival of MEKi-resistant melanoma cells. Combined MEK/autophagy inhibition also reduced the invasive and metastatic potential of MEKi-resistant cells in an in vivo zebrafish xenograft.. These results highlight a novel mechanism of MEKi-induced drug resistance and suggest that targeting autophagy may be a translatable approach to resensitize drug-resistant melanoma cells to the cytotoxic effects of MEKi.

    Topics: Animals; Apoptosis; Autophagy; Biomarkers, Tumor; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Neoplasm Recurrence, Local; Nerve Tissue Proteins; Nevus; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptors, Nerve Growth Factor; RNA-Binding Proteins; Skin; Skin Neoplasms; Xenograft Model Antitumor Assays; Zebrafish

2019
Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer.
    Oncogene, 2019, Volume: 38, Issue:10

    Despite showing clinical activity in BRAF-mutant melanoma, the MEK inhibitor (MEKi) trametinib has failed to show clinical benefit in KRAS-mutant colorectal cancer. To identify mechanisms of resistance to MEKi, we employed a pharmacogenomic analysis of MEKi-sensitive versus MEKi-resistant colorectal cancer cell lines. Strikingly, interferon- and inflammatory-related gene sets were enriched in cell lines exhibiting intrinsic and acquired resistance to MEK inhibition. The bromodomain inhibitor JQ1 suppressed interferon-stimulated gene (ISG) expression and in combination with MEK inhibitors displayed synergistic effects and induced apoptosis in MEKi-resistant colorectal cancer cell lines. ISG expression was confirmed in patient-derived organoid models, which displayed resistance to trametinib and were resensitized by JQ1 co-treatment. In in vivo models of colorectal cancer, combination treatment significantly suppressed tumor growth. Our findings provide a novel explanation for the limited response to MEK inhibitors in KRAS-mutant colorectal cancer, known for its inflammatory nature. Moreover, the high expression of ISGs was associated with significantly reduced survival of colorectal cancer patients. Excitingly, we have identified novel therapeutic opportunities to overcome intrinsic and acquired resistance to MEK inhibition in colorectal cancer.

    Topics: Animals; Azepines; Cell Line, Tumor; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Interferons; Mice; Mutation; Organoids; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Triazoles; Xenograft Model Antitumor Assays

2019
A case of recurrent histiocytic sarcoma with MAP2K1 pathogenic variant treated with the MEK inhibitor trametinib.
    International journal of hematology, 2019, Volume: 109, Issue:2

    Histiocytic sarcoma in advanced clinical stages is typically an aggressive neoplasm, with poor response to conventional chemotherapy. An 18-year-old male with refractory histiocytic sarcoma that had transformed from Rosai-Dorfman disease was admitted to our hospital. A pathogenic variant of MAP2K1 was detected by next-generation sequencing of tumor specimens. Affected regions showed excellent responses to the MEK inhibitor trametinib. It has been reported that RAS/MEK/ERK pathway is activated in many cases of histiocytic sarcoma. MEK inhibition may represent a useful treatment option in histiocytic sarcoma.

    Topics: Adolescent; Histiocytic Sarcoma; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Signaling System; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Recurrence; Treatment Outcome

2019
Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study.
    Melanoma research, 2019, Volume: 29, Issue:1

    BRAF and MEK kinase inhibitors can be highly effective in treating BRAF-mutant melanomas, but their safety and activity in patients with active/symptomatic brain metastases are unclear. We sought to shed light on this open clinical question. We conducted a multicenter retrospective study on real-life patients with melanoma and active brain metastases treated with combination BRAF/MEK inhibitors. A total of 65 patients were included (38 men and 27 women; median age: 49 years). Of them, 53 patients received dabrafenib/trametinib, 10 received vemurafenib/cobimetinib, one received encorafenib/binimetinib, and one received vemurafenib/trametinib. We did not observe any unexpected treatment-related safety signals in our cohort. Overall, 17 patients continued on therapy through the cutoff date. After initiation of therapy, steroid dose could be decreased in 22 of 33 patients (11 tapered off entirely), anticonvulsants were stopped in four of 21, and narcotics were stopped in four of 12. Median progression-free survival from the start of therapy was 5.3 months (95% confidence interval: 3.6-6.1), and median overall survival was 9.5 months (95% confidence interval: 7.7-13.5). A total of 20 patients were surviving at the cutoff date. Univariate analysis of age, sex, ulceration status, thickness, stage, location, or lactate dehydrogenase did not reveal significant predictors of progression-free survival or overall survival within our cohort, but multivariate analysis suggested that older age, lower risk location of original lesion, and nodular melanoma are poor prognostic indicators. Combination therapy with BRAF/MEK inhibitors is a viable treatment option for patients with BRAF-mutant melanoma and brain metastases, but further studies should help to define the optimal treatment approach in this population.

    Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Brain Neoplasms; Female; Follow-Up Studies; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Oximes; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Survival Rate; Young Adult

2019
Computational Immune Monitoring Reveals Abnormal Double-Negative T Cells Present across Human Tumor Types.
    Cancer immunology research, 2019, Volume: 7, Issue:1

    Advances in single-cell biology have enabled measurements of >40 protein features on millions of immune cells within clinical samples. However, the data analysis steps following cell population identification are susceptible to bias, time-consuming, and challenging to compare across studies. Here, an ensemble of unsupervised tools was developed to evaluate four essential types of immune cell information, incorporate changes over time, and address diverse immune monitoring challenges. The four complementary properties characterized were (i) systemic plasticity, (ii) change in population abundance, (iii) change in signature population features, and (iv) novelty of cellular phenotype. Three systems immune monitoring studies were selected to challenge this ensemble approach. In serial biopsies of melanoma tumors undergoing targeted therapy, the ensemble approach revealed enrichment of double-negative (DN) T cells. Melanoma tumor-resident DN T cells were abnormal and phenotypically distinct from those found in nonmalignant lymphoid tissues, but similar to those found in glioblastoma and renal cell carcinoma. Overall, ensemble systems immune monitoring provided a robust, quantitative view of changes in both the system and cell subsets, allowed for transparent review by human experts, and revealed abnormal immune cells present across multiple human tumor types.

    Topics: Adenoids; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Female; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Middle Aged; Monitoring, Immunologic; Neoplasms; Oximes; Palatine Tonsil; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; T-Lymphocytes

2019
Zoledronic acid enhances the efficacy of the MEK inhibitor trametinib in KRAS mutant cancers.
    Cancer letters, 2019, 02-01, Volume: 442

    KRAS mutation is the most common type of mutation in human cancers. However, the direct pharmacological inhibition of KRAS has not been clinically successful. Trametinib (GSK1120212, Tram), a newer MEK inhibitor, inhibits RAS signaling through mitogen-activated protein kinase (MAPK) cascade suppression. The effectiveness of Tram in clinical practice is limited in KRAS mutant tumors compared to that in BRAF mutant tumors. Here, we found that Tram treatment provoked feedback activation of upstream RAS, thus causing an induction of phosphorylated MEK (pMEK) and phosphorylated ERK (pERK) rebound in KRAS mutant tumors. This failure of persistent ERK inhibition led to drug resistance. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, disrupts the biological activity of RAS by inhibiting its isoprenylation. Surprisingly, ZA overcame Tram resistance, and augmented antitumor activity was observed in KRAS mutant tumors both in vitro and in vivo. Furthermore, ZA enhanced the effect of Tram partially through the mevalonate pathway. In summary, the combination of the two FDA-approved drugs Tram and ZA may represent a novel therapeutic strategy for the treatment of KRAS mutant cancers.

    Topics: A549 Cells; Animals; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Female; HCT116 Cells; HT29 Cells; Humans; Mevalonic Acid; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Protein Prenylation; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays; Zoledronic Acid

2019
Study of Molecular Mechanism of the Interaction Between MEK1/2 and Trametinib with Docking and Molecular Dynamic Simulation.
    Interdisciplinary sciences, computational life sciences, 2019, Volume: 11, Issue:1

    Trametinib was endorsed by the FDA in 2013 as a single agent for adult melanoma patients. Trametinib inhibits cell growth and proliferation in multiple tumor xenografts by preventing RAF phosphorylation of MEK and thus restricting accumulation of activated MEK. In this study, the focus of investigation was the mechanism of the interaction between trametinib and MEK1/2 via computational simulation. To specify the best interaction site of inhibitor with MEK1/2 based on the interaction energy ranking, first we performed a docking and then we studied the interactions of the ATP-bound MEK with trametinib, with RAF and the complex of the ATP-bound MEK-trametinib with RAF via molecular dynamic simulations. The results showed that trametinib inactivates the enzyme by bonding to a group of amino acids including Lys97/101, SER218/216, Asp208/212, and Met143/147 in MEK1/2. By bonding to the essential amino acids, trametinib inhibits the activity of the enzyme. All in all, the acquired results can be of great use in designing new inhibitors.

    Topics: MAP Kinase Kinase 1; MAP Kinase Kinase 2; Molecular Dynamics Simulation; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2019
Targeted treatment of metastatic melanoma in a drug-addicted patient with pre-existing hepatitis C.
    Dermatologic therapy, 2019, Volume: 32, Issue:2

    Topics: Adult; Amphetamine-Related Disorders; Antineoplastic Combined Chemotherapy Protocols; Hepatitis C; Humans; Imidazoles; Male; Melanoma; Molecular Targeted Therapy; Neoplasm Metastasis; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

2019
Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1-based therapy.
    Cancer, 2019, 03-15, Volume: 125, Issue:6

    Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for patients with BRAF V600-mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the post-programmed cell death protein 1 (PD-1) setting.. Patients with BRAF V600-mutant melanoma who received combined BRAF-MEK after prior PD-1-based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan-Meier methods from the time of the initiation of BRAF-MEK therapy.. A total of 78 patients were identified as having received a BRAF-MEK regimen at a median of 34 days after the last dose of PD-1-based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty-five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF-MEK <90 days after the last dose of PD-1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE-related hospitalization. Among 55 BRAF-naive patients, the median time receiving BRAF-MEK therapy was 5.8 months and the median OS was 15.6 months.. The majority of patients receiving BRAF-MEK inhibition after PD-1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Australia; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Analysis; Tertiary Care Centers; Treatment Outcome; United States

2019
The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling.
    Journal of the American Society of Nephrology : JASN, 2019, Volume: 30, Issue:1

    During kidney fibrosis, a hallmark and promoter of CKD (regardless of the underlying renal disorder leading to CKD), the extracellular-regulated kinase 1/2 (ERK1/2) pathway, is activated and has been implicated in the detrimental differentiation and expansion of kidney fibroblasts. An ERK1/2 pathway inhibitor, trametinib, is currently used in the treatment of melanoma, but its efficacy in the setting of CKD and renal fibrosis has not been explored.. We investigated whether trametinib has antifibrotic effects in two mouse models of renal fibrosis-mice subjected to unilateral ureteral obstruction (UUO) or fed an adenine-rich diet-as well as in cultured primary human fibroblasts. We also used immunoblot analysis, immunohistochemical staining, and other tools to study underlying molecular mechanisms for antifibrotic effects.. Trametinib significantly attenuated collagen deposition and myofibroblast differentiation and expansion in UUO and adenine-fed mice. We also discovered that in injured kidneys, inhibition of the ERK1/2 pathway by trametinib ameliorated mammalian target of rapamycin complex 1 (mTORC1) activation, another key profibrotic signaling pathway. Trametinib also inhibited the ERK1/2 pathway in cultured primary human renal fibroblasts stimulated by application of TGF-. Further study of trametinib as a potential candidate for the treatment of chronic renal fibrotic diseases of diverse etiologies is warranted.

    Topics: Animals; Biopsy, Needle; Cells, Cultured; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Fibrosis; Immunohistochemistry; Mechanistic Target of Rapamycin Complex 1; Mice; Molecular Targeted Therapy; Pyridones; Pyrimidinones; Random Allocation; Reference Values; Renal Insufficiency, Chronic; Signal Transduction

2019
Improvement of hereditary palmoplantar keratoderma with oral trametinib.
    Pediatric dermatology, 2019, Volume: 36, Issue:1

    We report a child with a past medical history notable for congenital deafness, palmoplantar keratoderma (PPK), and hypothalamic glioma who initiated a MEK inhibitor trametinib for cancer-directed therapy at 11 years of age and was incidentally noted to have marked improvement in his PPK. Trametinib withdrawal led to worsening in the patient's PPK. We speculate that the patient's PPK improved because of trametinib, given the temporal relationship between trametinib therapy and PPK severity, observed both after introduction and withdrawal of trametinib therapy. The upregulation of MAPK signaling may be involved in the pathogenesis of keratinocyte proliferation in at least some forms of PPK, given that downstream inhibition of MAPK signaling led to an improvement in the patient's PPK.

    Topics: Administration, Oral; Adolescent; Humans; Keratoderma, Palmoplantar; Male; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2019
Genotype-Guided Medical Treatment of an Arteriovenous Malformation in a Child.
    JAMA dermatology, 2019, 02-01, Volume: 155, Issue:2

    Topics: Arteriovenous Malformations; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Genotype; Humans; Microtubule-Associated Proteins; Molecular Targeted Therapy; Pyridones; Pyrimidinones; Severity of Illness Index; Thoracic Wall; Treatment Outcome

2019
Adverse Event Management in Patients with
    The oncologist, 2019, Volume: 24, Issue:7

    Therapies for advanced non-small cell lung cancer (NSCLC) continue to become more sophisticated. Chemotherapeutics are giving way to newer approaches such as immune checkpoint inhibitors and targeted therapies for greater efficacy and improved outcomes. Dabrafenib plus trametinib combination therapy was first approved for the treatment of metastatic melanoma harboring the

    Topics: Adenocarcinoma of Lung; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Disease Management; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Imidazoles; Lung Neoplasms; Male; Middle Aged; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Rate

2019
The real-world impact of modern treatments on the survival of patients with metastatic melanoma.
    European journal of cancer (Oxford, England : 1990), 2019, Volume: 108

    Between 2010 and 2015, pivotal trials with strict enrolment criteria led to the approval of several new treatments for metastatic melanoma (MM). We sought to determine the impact of these treatments in the 'real world'. We took advantage of the Danish MM database (DAMMED), which contains data on the entire, unselected population diagnosed with MM within Denmark. All MM cases (excluding ocular MM, n = 837) diagnosed in three non-consecutive years marked by major changes in the first-line treatments (2012: interleukin-2 and BRAF inhibitors; 2014: anti-CTLA-4: Cytotoxic T-Lymphocyte Antigen 4 and 2016: anti-PD-1: programmed cell death protein 1 and MEK inhibitors) were retrieved. Patients were grouped into 'trial-like' and 'trial-excluded' based on the common trial eligibility criteria. In the 'trial-like' population (39% of all MM), the median overall survival (OS) was not reached in 2016 versus 18.8 months in 2014 (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.35-0.75; p = 0.0005) and 16.5 months in 2012 (HR 0.41, 95% CI 0.27-0.63; p < 0.0001). In the 'trial-excluded' population (61% of all MM), 75% had brain metastases and/or (performance status) PS ≥ 2. Here, the median OS improved to 6.9 months in 2016 versus 5.2 months in 2014 (HR 0.66, 95% CI 0.52-0.84; p = 0.0008) and 4.2 months in 2012 (HR 0.66, 95% CI 0.52-0.84; p = 0.0007). Subgroup analysis of the BRAF wild-type population showed an improved 1-year survival rate in 2016 versus 2014 (35.9% vs 18.8%, p = 0.0153). In conclusion, the introduction of modern treatments has led to an improved survival of real-world patients with MM, regardless of their eligibility to clinical trials and the BRAF status. These data support the application of modern treatments to patient populations which are not represented in pivotal trials.

    Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Immunological; Denmark; Female; Humans; Imidazoles; Ipilimumab; Male; Melanoma; Nivolumab; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Rate; Temozolomide

2019
Preclinical assessment of MEK1/2 inhibitors for neurofibromatosis type 2-associated schwannomas reveals differences in efficacy and drug resistance development.
    Neuro-oncology, 2019, 03-18, Volume: 21, Issue:4

    Neurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas.. Mouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns.. Trametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance.. MEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.

    Topics: Animals; Antineoplastic Agents; Azetidines; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mice; Neurofibromatosis 2; Neuroma, Acoustic; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2019
Severe rhabdomyolysis developing in an advanced melanoma patient treated by pembrolizumab followed by dabrafenib trametinib combined therapy.
    The Journal of dermatology, 2019, Volume: 46, Issue:7

    Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemokine CXCL5; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Prognosis; Pyridones; Pyrimidinones; Rhabdomyolysis; Severity of Illness Index; Skin Neoplasms

2019
Sudden elevation of plasma D-dimer levels induced by the combination therapy of dabrafenib and trametinib: Report of two cases.
    The Journal of dermatology, 2019, Volume: 46, Issue:4

    The combination therapy of dabrafenib and trametinib revolutionized the treatment for BRAF V600-mutated melanoma. Various adverse events have been reported for this treatment, most notably fever. Herein, we report two cases of novel an adverse event, namely sudden and significant elevation of plasma D-dimer level induced by this therapy. In the first case, the remarkable elevation of plasma D-dimer level up to 87.4 mg/dL was noted on day 11, and in the second case, the plasma D-dimer level reached 125.5 mg/dL on day 25. In both cases, D-dimer levels gradually decreased after the cessation of this therapy. Although the exact cause is not clear, we assume two possible hypotheses: the first is that the combination therapy may induce disseminated intravascular coagulation, and the second is that the therapy induced pathological condition of secondary thrombotic microangiopathies. Our cases suggest that this thrombotic adverse event should not be overlooked, and coagulation parameters need to be monitored during the course of this treatment.

    Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Fatigue; Female; Fever; Fibrin Fibrinogen Degradation Products; Humans; Imidazoles; Melanoma; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Vomiting

2019
Sweet syndrome in metastatic melanoma during treatment with dabrafenib and trametinib.
    The Australasian journal of dermatology, 2019, Volume: 60, Issue:3

    Topics: Antineoplastic Agents; Female; Humans; Imidazoles; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Sweet Syndrome

2019
Case series of dabrafenib-trametinib-induced pyrexia successfully treated with colchicine.
    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 2019, Volume: 27, Issue:10

    The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71% of patients. Pyrexia resulted in therapy discontinuation in up to 26% of patients that otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. Based on preliminary data by our group suggesting an upregulation of the mitogen-activated protein kinases (MAPKs) in human lymphocytes exposed to dabrafenib and trametinib, specifically elevated expression of phosphorylated JNK (p-JNK), p38 MAPK (p-p38 MAPK), and ERK5 (p-ERK5), we hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy in which the MAPK pathway is hyper-activated. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Colchicine; Enzyme Activation; Fever; Humans; Imidazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Oximes; Pyridones; Pyrimidinones

2019
Inhibition of MEK suppresses hepatocellular carcinoma growth through independent MYC and BIM regulation.
    Cellular oncology (Dordrecht), 2019, Volume: 42, Issue:3

    Hepatocellular carcinoma (HCC) is an aggressive malignancy. In HCC, mitogen-activated protein kinase (MAPK) signaling is overactivated. The MAPK kinase (MEK) inhibitor trametinib has been approved to treat several types of advanced cancers with a BRAF mutation. Herein, we examined whether trametinib has efficacy against HCC.. The effects of trametinib on cell viability, proliferation and tumor growth were assessed in HCC-derived cell lines and mouse xenograft models. Western blot analysis and immunohistochemistry were used to identify key regulators critical for HHC cell proliferation and tumor growth.. We found that trametinib dose-dependently inhibited the viability and proliferation of HCC cells. We also found that a strong suppression of MEK by trametinib downregulated the pro-survival protein MYC, but upregulated the pro-apoptotic protein BIM. This dual differential regulation of MYC and BIM was found to be accompanied by upregulation of a MYC-targeted cyclin dependent kinase inhibitor, p27. Collectively, our data indicate that trametinib exhibits efficacy in treating HCC cells via distinct regulation of the MYC and BIM pathways. As such, targeting MEK to block MAPK signaling with trametinib may provide novel treatment opportunities for HCC.

    Topics: Animals; Bcl-2-Like Protein 11; Carcinoma, Hepatocellular; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Pyridones; Pyrimidinones; Tumor Burden; Xenograft Model Antitumor Assays

2019
Giant Congenital Melanocytic Nevus Treated With Trametinib.
    Pediatrics, 2019, Volume: 143, Issue:3

    Giant congenital nevi are melanocytic proliferations of the skin that may be complicated by melanoma, neurocutaneous melanocytosis, pain, pruritus, and disfigurement. Current treatment options include surgical resection and medical management of associated symptoms. There is limited efficacy in these modalities. No effective pharmacologic treatments are available for the treatment of these lesions. We present the case of a 7-year-old girl with a giant congenital melanocytic nevus that had an

    Topics: Antineoplastic Agents; Child; Female; Humans; Nevus, Pigmented; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2019
Neurotoxicity induced by targeted therapies in patients treated for metastatic melanoma.
    European journal of cancer (Oxford, England : 1990), 2019, Volume: 111

    Topics: Aged; Antineoplastic Agents; Azetidines; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Oximes; Piperidines; Polyneuropathies; Pyridones; Pyrimidinones; Skin Neoplasms; Vemurafenib

2019
MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer.
    Prostate cancer and prostatic diseases, 2019, Volume: 22, Issue:4

    Metastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with the goal of identifying candidate drugs for rapid translation into proof of concept Phase II trials in mCRPC.. To identify evidence of activation of druggable kinases in these patients, we compared mRNA expression from metastatic biopsies of patients with mCRPC (n = 101) to mRNA expression in localized prostate from TCGA and used this analysis to infer differential kinase activity. In addition, we assessed the differential phosphorylation levels for key MAPK pathway kinases between mCRPC and localized prostate cancers.. Transcriptomic profiling of 101 patients with mCRPC as compared to patients with localized prostate cancer identified evidence of hyperactive ERK1, and whole genome sequencing revealed frequent amplifications of members of the MAPK pathway in 32% of this cohort. Next, we confirmed elevated levels of phosphorylated ERK1/2 in castration resistant prostate cancer as compared to untreated primary prostate cancer. We observed that the presence of detectable phosphorylated ERK1/2 in the primary tumor is associated with biochemical failure after radical prostatectomy independent of clinicopathologic features. ERK1 is the immediate downstream target of MEK1/2, which is druggable with trametinib, an approved therapeutic for melanoma. Trametinib elicited a profound biochemical and clinical response in a patient who had failed multiple prior treatments for mCRPC.. We conclude that pharmacologic targeting of the MEK/ERK pathway may be a viable treatment strategy for patients with refractory metastatic prostate cancer. An ongoing Phase II trial tests this hypothesis.

    Topics: Aged; Antineoplastic Agents; Biopsy; Disease-Free Survival; Gene Amplification; Gene Expression Regulation, Neoplastic; Humans; Male; MAP Kinase Signaling System; Middle Aged; Mitogen-Activated Protein Kinase 3; Molecular Targeted Therapy; Phosphorylation; Prospective Studies; Prostate; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; RNA-Seq

2019
Cutaneous reactions to targeted therapies in children with CNS tumors: A cross-sectional study.
    Pediatric blood & cancer, 2019, Volume: 66, Issue:6

    MAPK (RAS-RAF-MEK-ERK-MAP) and mTOR inhibitors are novel treatments for pediatric central nervous system (CNS) tumors. The literature on common cutaneous adverse reactions to these therapies is sparse in the pediatric population. The aim of this study was to describe common cutaneous adverse reactions to BRAF, MEK, and mTOR inhibitors in children with CNS tumors.. In this cross-sectional study, patients younger than 21 years of age receiving BRAF, MEK, and mTOR inhibitor monotherapy for a CNS tumor were enrolled over a one-year period. Full body skin examination, photographs of dermatologic findings, and initial treatment recommendations were included at the initial visit, and follow-up skin examinations were recommended every three months.. Twenty-two patients were enrolled in the study. Fifty percent (11/22) received trametinib, a MEK inhibitor, 27.3% (6/22) received dabrafenib, a BRAF inhibitor, and 22.7% (5/22) received everolimus, an mTOR inhibitor. Median age at visit was 11 years (range, 3-19). Median time from treatment initiation to skin examination was 4.5 months (range, 0-43). Ninety-six percent (21/22) of all patients had at least one skin reaction. The most common reactions across treatment groups included follicular/acneiform eruptions and xerosis. Two patients on MEK inhibitors and one patient on a BRAF inhibitor required therapy cessation due to severe cutaneous reactions.. Cutaneous reactions to targeted anticancer therapy in children are common, treatable, and rarely require drug dose reduction or discontinuation. Routine surveillance and early intervention may improve quality of life and facilitate continuation of life-saving therapy.

    Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Child; Child, Preschool; Cross-Sectional Studies; Drug Eruptions; Female; Follow-Up Studies; Humans; Imidazoles; Male; Molecular Targeted Therapy; Oximes; Prognosis; Pyridones; Pyrimidinones; Skin Diseases; Young Adult

2019
Targeting the MAPK pathway in advanced BRAF wild-type melanoma.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2019, 04-01, Volume: 30, Issue:4

    Topics: Humans; Indazoles; Melanoma; Paclitaxel; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones; Sulfonamides

2019
MEK nuclear localization promotes YAP stability via sequestering β-TrCP in KRAS mutant cancer cells.
    Cell death and differentiation, 2019, Volume: 26, Issue:11

    Tumours manage to survive the ablation of mutant KRAS, despite the development of KRAS-targeted drugs. Here we describe that inhibition of mutant KRAS promotes MEK nuclear localization as an alternative mechanism of KRAS-targeted drugs resistance. Tissue microarray analysis in colon tumours shows that aberrant MEK nuclear localization is closely related to YAP levels and tumour malignancy. MEK nuclear localization could sequester β-TrCP from cytoplasmic inactive YAP, then stabilizing YAP. Mutant KRAS restrains MEK within the cytoplasm via IQGAP1, inhibiting MEK nuclear translocation. Trametinib, an allosteric MEK inhibitor, could prevent MEK nuclear localization and subsequently promote YAP degradation. In vitro and in vivo results suggests that inhibition of MEK nuclear localization by trametinib synergizes with KRAS knockdown or deltarasin treatment in suppressing the viability of KRAS mutant colon cancer cells. Our study provides new insights into the mechanisms of resistance to KRAS ablation, and suggests novel strategies for the treatment of KRAS-mutant colon cancers.

    Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Benzimidazoles; beta-Transducin Repeat-Containing Proteins; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Female; HeLa Cells; Humans; MAP Kinase Kinase 1; Mice; Mice, Inbred BALB C; Mice, Nude; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Transcription Factors; YAP-Signaling Proteins

2019
Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers.
    Nature medicine, 2019, Volume: 25, Issue:4

    Topics: Animals; Autophagy; CA-19-9 Antigen; Cell Line, Tumor; Chloroquine; Humans; MAP Kinase Signaling System; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Pancreatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; ras Proteins; Xenograft Model Antitumor Assays

2019
Trametinib Attenuates Delayed Rejection and Preserves Thymic Function in Rat Lung Transplantation.
    American journal of respiratory cell and molecular biology, 2019, Volume: 61, Issue:3

    Delayed immunological rejection after human lung transplantation causes chronic lung allograft dysfunction, which is associated with high mortality. Delayed rejection may be attributable to indirect alloantigen presentation by host antigen-presenting cells; however, its pathophysiology is not fully understood. The mitogen-activated protein kinase pathway is activated in T cells upon stimulation, and we previously showed that the MEK inhibitor, trametinib, suppresses graft-versus-host disease after murine bone marrow transplantation. We investigated whether trametinib suppresses graft rejection after two types of rat lung transplantation and analyzed its immunological mode of action. Major histocompatibility complex-mismatched transplantation from brown Norway rats into Lewis rats and minor histocompatibility antigen-mismatched transplantation from Fischer 344 rats into Lewis rats were performed. Cyclosporine (CsA) and/or trametinib were administered alone or consecutively. Acute and delayed rejection, lymphocyte infiltration, and pulmonary function were evaluated. Administration of trametinib after CsA suppressed delayed rejection, reduced inflammatory cell infiltration and fibrosis within the graft, and preserved pulmonary functions at Day 28. Trametinib suppressed functional differentiation of T and B cells in the periphery but preserved thymic T cell differentiation. Donor B cells within the graft disappeared by Day 14, indicating that delayed graft rejection at Day 28 was mainly due to indirect presentation by host antigen-presenting cells. Finally, trametinib administration without CsA preconditioning suppressed rejection after minor histocompatibility antigen-mismatched transplantation. Trametinib attenuates delayed rejection upon major histocompatibility complex-mismatched transplantation by suppressing indirect presentation and is a promising candidate to treat chronic lung allograft dysfunction in humans.

    Topics: Animals; Cyclosporine; Graft Rejection; Lung; Lung Transplantation; Pyridones; Pyrimidinones; Rats, Inbred Lew; Transplantation, Homologous

2019
Modeling differentiation-state transitions linked to therapeutic escape in triple-negative breast cancer.
    PLoS computational biology, 2019, Volume: 15, Issue:3

    Drug resistance in breast cancer cell populations has been shown to arise through phenotypic transition of cancer cells to a drug-tolerant state, for example through epithelial-to-mesenchymal transition or transition to a cancer stem cell state. However, many breast tumors are a heterogeneous mixture of cell types with numerous epigenetic states in addition to stem-like and mesenchymal phenotypes, and the dynamic behavior of this heterogeneous mixture in response to drug treatment is not well-understood. Recently, we showed that plasticity between differentiation states, as identified with intracellular markers such as cytokeratins, is linked to resistance to specific targeted therapeutics. Understanding the dynamics of differentiation-state transitions in this context could facilitate the development of more effective treatments for cancers that exhibit phenotypic heterogeneity and plasticity. In this work, we develop computational models of a drug-treated, phenotypically heterogeneous triple-negative breast cancer (TNBC) cell line to elucidate the feasibility of differentiation-state transition as a mechanism for therapeutic escape in this tumor subtype. Specifically, we use modeling to predict the changes in differentiation-state transitions that underlie specific therapy-induced changes in differentiation-state marker expression that we recently observed in the HCC1143 cell line. We report several statistically significant therapy-induced changes in transition rates between basal, luminal, mesenchymal, and non-basal/non-luminal/non-mesenchymal differentiation states in HCC1143 cell populations. Moreover, we validate model predictions on cell division and cell death empirically, and we test our models on an independent data set. Overall, we demonstrate that changes in differentiation-state transition rates induced by targeted therapy can provoke distinct differentiation-state aggregations of drug-resistant cells, which may be fundamental to the design of improved therapeutic regimens for cancers with phenotypic heterogeneity.

    Topics: Antineoplastic Agents; Biomarkers, Tumor; Cell Death; Cell Differentiation; Cell Division; Cell Line, Tumor; Dimethyl Sulfoxide; Epithelial-Mesenchymal Transition; Female; Humans; Imidazoles; Models, Biological; Pyridones; Pyrimidinones; Quinolines; Triple Negative Breast Neoplasms

2019
Preclinical Efficacy of Covalent-Allosteric AKT Inhibitor Borussertib in Combination with Trametinib in
    Cancer research, 2019, 05-01, Volume: 79, Issue:9

    Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Proliferation; Colorectal Neoplasms; Drug Therapy, Combination; Female; Humans; Mice; Mice, Nude; Mutation; Pancreatic Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2019
Redifferentiation of a
    Thyroid : official journal of the American Thyroid Association, 2019, Volume: 29, Issue:5

    Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Differentiation; Female; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Neoplasms

2019
Clinical protein science in translational medicine targeting malignant melanoma.
    Cell biology and toxicology, 2019, Volume: 35, Issue:4

    Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry-based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive

    Topics: Biological Specimen Banks; Biomarkers, Tumor; Drug Resistance, Neoplasm; Humans; Imidazoles; Melanoma; Melanoma, Cutaneous Malignant; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Proteomics; Pyridones; Pyrimidinones; Skin Neoplasms; Translational Research, Biomedical

2019
Mesothelin and TGF-α predict pancreatic cancer cell sensitivity to EGFR inhibitors and effective combination treatment with trametinib.
    PloS one, 2019, Volume: 14, Issue:3

    Clinical trials of EGFR inhibitors in combination with gemcitabine for the treatment of pancreatic ductal adenocarcinoma (PDAC) have generated mixed results partially due to the poorly defined effectiveness of EGFR inhibitors in PDAC. Here, we studied a panel of PDAC cell lines to compare the IC50s of the EGFR inhibitors gefitinib and cetuximab. We found that gefitinib induced biphasic inhibition in over 50% of PDAC cells, with the initial growth inhibition occurring at nanomolar concentrations and a second growth inhibition occurring outside the clinical range. In contrast to gefitinib, cetuximab produced a single phase growth inhibition in a subset of PDAC cells. Using this sensitivity data, we screened for correlations between cell morphology proteins and EGFR ligands to EGFR inhibitor sensitivity, and found that mesothelin and the EGFR ligand TGF-α have a strong correlation to gefitinib and cetuximab sensitivity. Analysis of downstream signaling pathways indicated that plc-γ1 and c-myc were consistently inhibited by EGFR inhibitor treatment in sensitive cell lines. While an inconsistent additive effect was observed with either cetuximab or gefitinib in combination with gemcitabine, the cell pathway data indicated consistent ERK activation, leading us to pursue EGFR inhibitors in combination with trametinib, a MEK1/2 inhibitor. Both cetuximab and gefitinib in combination with trametinib produced an additive effect in all EGFR sensitive cell lines. Our results indicate that mesothelin and TGF-α can predict PDAC sensitivity to EGFR inhibitors and a combination of EGFR inhibitors with trametinib could be a novel effective treatment for PDAC.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Cycle; Cell Proliferation; Cetuximab; Drug Resistance, Neoplasm; ErbB Receptors; Gefitinib; GPI-Linked Proteins; Humans; Mesothelin; Pancreatic Neoplasms; Pyridones; Pyrimidinones; Signal Transduction; Transforming Growth Factor alpha; Tumor Cells, Cultured

2019
Clinical Benefit From BRAF/MEK Inhibition in a Double Non-V600E BRAF Mutant Lung Adenocarcinoma: A Case Report.
    Clinical lung cancer, 2019, Volume: 20, Issue:3

    Topics: Adenocarcinoma of Lung; Aged; Antineoplastic Combined Chemotherapy Protocols; High-Throughput Nucleotide Sequencing; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Remission Induction; Treatment Outcome

2019
Conclusions from quality of life studies in patients with resected high-risk melanoma: one part of the full story.
    The Lancet. Oncology, 2019, Volume: 20, Issue:5

    Topics: Humans; Imidazoles; Melanoma; Mutation; Oximes; Patient Reported Outcome Measures; Pyridones; Pyrimidinones; Quality of Life

2019
Reply to E. Hindié and K.R. Hess.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2019, 05-20, Volume: 37, Issue:15

    Topics: Follow-Up Studies; Humans; Imidazoles; Melanoma; Neoplasm Recurrence, Local; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2019
What Is the Role of Dabrafenib Plus Trametinib Adjuvant Therapy in Stage IIIA Melanoma?
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2019, 05-20, Volume: 37, Issue:15

    Topics: Follow-Up Studies; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2019
Beneficial Effect of Adjuvant Dabrafenib Plus Trametinib on Recurrence-Free Survival in Patients With Resected
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2019, 05-20, Volume: 37, Issue:15

    Topics: Follow-Up Studies; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2019
Panniculitis and vitiligo occurring during BRAF and MEK inhibitors combination in advanced melanoma patients: Potential predictive role of treatment efficacy.
    PloS one, 2019, Volume: 14, Issue:4

    Panniculitis and vitiligo-like lesions have been recently identified as rare cutaneous side effects of the combination of BRAF and MEK inhibitors, a standard of care in metastatic and locally advanced BRAF V600 mutated melanoma. An immune-mediated mechanism has been advocated in the pathogenesis of these skin lesions. Herein we retrospectively reviewed our institutional experience with the aim to explore the association between the occurrence of panniculitis and vitiligo-like lesions during combination therapy with dabrafenib (D) and trametinib (T) and outcome of advanced melanoma patients. Among 52 consecutive BRAF V600 mutated melanoma patients submitted to DT in our center, 12 (23%) developed immune related skin lesions (IRSLs): 8 panniculitis and 4 vitiligo. Patients with IRSLs diagnosis obtained a better disease response (83% versus 25%) (p = 0.001) than their counterpart and had a longer progression free survival and overall survival. The association of IRSLs and lower risk of disease progression (HR 0.19; CI 95% 0.04-0.90; p = 0.043) was confirmed after adjusting for major prognostic factors in multivariate analysis. IRSLs might represent an easy predictive surrogate marker for treatment response and favourable outcome in melanoma patients submitted to DT combination therapy.

    Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mutation; Oximes; Panniculitis; Progression-Free Survival; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vitiligo

2019
Estimation of Distant Metastasis-free Survival in Trials of Adjuvant Therapy for Melanoma.
    The New England journal of medicine, 2019, 04-04, Volume: 380, Issue:14

    Topics: Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2019
BRAF-mutated, acral verrucous melanoma successfully treated by dabrafenib plus trametinib combination therapy.
    Clinical and experimental dermatology, 2019, Volume: 44, Issue:8

    Topics: Antineoplastic Combined Chemotherapy Protocols; Asian People; Dermoscopy; Female; Humans; Imidazoles; Lymph Node Excision; Lymph Nodes; Margins of Excision; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Warts

2019
Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer.
    Cancer research, 2019, 05-15, Volume: 79, Issue:10

    Topics: Animals; Antineoplastic Agents; Benzamides; Cell Division; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyridones; Pyrimidinones; Receptors, CXCR; Xenograft Model Antitumor Assays

2019
A Need for Targeted Immunosuppression after Lung Transplantation.
    American journal of respiratory cell and molecular biology, 2019, Volume: 61, Issue:3

    Topics: Animals; Immunosuppression Therapy; Lung Transplantation; Pyridones; Pyrimidinones; Rats

2019
Quantitative Size-Based Analysis of Tumor Spheroids and Responses to Therapeutics.
    Assay and drug development technologies, 2019, Volume: 17, Issue:3

    Drug resistance remains a major clinical problem despite advances in targeted therapies. In recent years, methods to culture cancer cells in three-dimensional (3D) environments to better mimic native tumors have gained increasing popularity. Nevertheless, unlike traditional two-dimensional (2D) cell cultures, analysis of 3D cultures is not straightforward. Most biochemical assays developed for 2D cultures have to be optimized for use with 3D cultures. We addressed this important problem by presenting a simple method of quantitative size-based analysis of growth and drug responses of 3D cultures of cancer cells as tumor spheroids. We used an aqueous two-phase system to form consistently sized tumor spheroids of colorectal cancer cells. Using spheroid images, we computed the size of spheroids over time and demonstrated that growth of spheroids from this analysis strongly correlates with that using a PrestoBlue biochemical assay optimized for 3D cultures. Next, we cyclically treated the tumor spheroids with a MEK inhibitor, trametinib, for 6-day periods with a recovery phase in between. This inhibitor was selected because of mutation of colon cancer cells in the MEK/ERK pathway. We used size measurements to evaluate the efficacy of trametinib and predict development of resistance of colon cancer cells during the cyclical treatment and recovery regimen. This size-based analysis closely matched the biochemical analysis of drug responses of spheroids. We performed molecular analysis and showed that resistance to trametinib emerged due to feedback activation of the PI3K/AKT signaling pathway. Therefore, we combined trametinib with a PI3K/AKT inhibitor, dactolisib, and demonstrated that size-based analysis of spheroids reliably allowed quantifying the effect of the combination treatment to prevent drug resistance. This study established that size measurements of spheroids can be used as a straightforward method for quantitative studies of drug responses of tumor spheroids and identifying drug combinations that block resistance.

    Topics: Antineoplastic Agents; Colorectal Neoplasms; Drug Combinations; Drug Resistance, Neoplasm; HCT116 Cells; HT29 Cells; Humans; Imidazoles; Particle Size; Pyridones; Pyrimidinones; Quinolines; Spheroids, Cellular; Tumor Cells, Cultured

2019
Pulsatile MEK Inhibition Improves Anti-tumor Immunity and T Cell Function in Murine Kras Mutant Lung Cancer.
    Cell reports, 2019, 04-16, Volume: 27, Issue:3

    KRAS is one of the driver oncogenes in non-small-cell lung cancer (NSCLC) but remains refractory to current modalities of targeted pathway inhibition, which include inhibiting downstream kinase MEK to circumvent KRAS activation. Here, we show that pulsatile, rather than continuous, treatment with MEK inhibitors (MEKis) maintains T cell activation and enables their proliferation. Two MEKis, selumetinib and trametinib, induce T cell activation with increased CTLA-4 expression and, to a lesser extent, PD-1 expression on T cells in vivo after cyclical pulsatile MEKi treatment. In addition, the pulsatile dosing schedule alone shows superior anti-tumor effects and delays the emergence of drug resistance. Furthermore, pulsatile MEKi treatment combined with CTLA-4 blockade prolongs survival in mice bearing tumors with mutant Kras. Our results set the foundation and show the importance of a combinatorial therapeutic strategy using pulsatile targeted therapy together with immunotherapy to optimally enhance tumor delay and promote long-term anti-tumor immunity.

    Topics: Animals; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; CTLA-4 Antigen; Disease Models, Animal; Female; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Survival Rate; T-Lymphocytes

2019
Prohibitin promotes de-differentiation and is a potential therapeutic target in neuroblastoma.
    JCI insight, 2019, 04-18, Volume: 5

    Gain of the long arm of chromosome 17 (17q) is a cytogenetic hallmark of high-risk neuroblastoma, yet its contribution to neuroblastoma pathogenesis remains incompletely understood. Combining whole-genome and RNA sequencing of neuroblastomas, we identified the prohibitin (PHB) gene as highly expressed in tumors with 17q gain. High PHB expression correlated with poor prognosis and was associated with loss of gene expression programs promoting neuronal development and differentiation. PHB depletion induced differentiation and apoptosis and slowed cell cycle progression of neuroblastoma cells, at least in part through impaired ERK1/2 activation. Conversely, ectopic expression of PHB was sufficient to increase proliferation of neuroblastoma cells and was associated with suppression of markers associated with neuronal differentiation and favorable neuroblastoma outcome. Thus, PHB is a 17q oncogene in neuroblastoma that promotes tumor cell proliferation, and de-differentiation.

    Topics: Animals; Apoptosis; Cell Cycle Checkpoints; Cell Dedifferentiation; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Child, Preschool; Chromosomes, Human, Pair 17; Humans; MAP Kinase Signaling System; Mice; Neuroblastoma; Prohibitins; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Repressor Proteins; RNA-Seq; RNA, Messenger; Sequence Analysis, RNA; Whole Genome Sequencing; Xenograft Model Antitumor Assays

2019
Response of BRAF
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2019, Volume: 14, Issue:5

    Topics: Adenocarcinoma of Lung; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Imidazoles; Lung Neoplasms; Male; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2019
Hypertrophic Cardiomyopathy in Noonan Syndrome Treated by MEK-Inhibition.
    Journal of the American College of Cardiology, 2019, 05-07, Volume: 73, Issue:17

    Topics: Cardiomyopathy, Hypertrophic; Female; Gestational Age; Humans; Infant, Newborn; MAP Kinase Kinase Kinase 1; Mutation; Noonan Syndrome; Pregnancy; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Rare Diseases; Risk Assessment; Sampling Studies; Treatment Outcome; Ultrasonography, Prenatal

2019
Identifying the ErbB/MAPK Signaling Cascade as a Therapeutic Target in Canine Bladder Cancer.
    Molecular pharmacology, 2019, Volume: 96, Issue:1

    Topics: Animals; Carcinoma, Transitional Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dog Diseases; Dogs; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; HT29 Cells; Humans; MAP Kinase Signaling System; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quinazolines; Urinary Bladder Neoplasms; Vemurafenib

2019
Efficacy and Safety of BRAF Inhibitors With or Without MEK Inhibitors in BRAF-Mutant Advanced Non-Small-Cell Lung Cancer: Findings From a Real-Life Cohort.
    Clinical lung cancer, 2019, Volume: 20, Issue:4

    Real-life comparative data on BRAF inhibitors (BRAFi) and BRAFi + MEK inhibitors (MEKi) combination in BRAF-mutant (BRAFm) non-small-cell lung cancer (NSCLC) is lacking.. Consecutive BRAFm advanced NSCLC patients (n = 58) treated in 9 Israeli centers in 2009-2018 were identified. These were divided according to mutation subtype and treatment into groups A1 (V600E, BRAFi; n = 5), A2 (V600E, BRAFi + MEKi; n = 15), A3 (V600E, no BRAFi; n = 7), B1 (non-V600E, BRAFi ± MEKi; n = 7), and B2 (non-V600E, no BRAFi; n = 23); one patient received both BRAFi and BRAFi + MEKi. Safety, objective response rate, progression-free survival with BRAFi ± MEKi, and overall survival were assessed.. Objective response rate was 40%, 67%, and 33% in groups A1, A2, and B1, respectively (P = .5 for comparison between groups A1 and A2). In group B1, G469A and L597R mutations were associated with response to BRAFi + MEKi. Median progression-free survival was 1.2 months (95% confidence interval [CI], 0.5-5.3), 5.5 months (95% CI, 0.7-9.3), and 3.6 months (95% CI, 1.5-6.7) for groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P = .04). Median overall survival with BRAFi ± MEKi was 1.7 months (95% CI, 0.5-NR), 9.5 months (95% CI, 0.2-14.9), and 7.1 months (95% CI, 1.8-NR) in groups A1, A2, and B1, respectively (log-rank for comparison between groups A1 and A2, P = .6). Safety profiles differed slightly, and similar treatment discontinuation rates were observed with BRAFi and BRAFi + MEKi.. In the real-life setting, activity and safety of BRAFi + MEKi in V600E BRAFm NSCLC are comparable to those observed in prospective clinical trials; the combination of BRAFi + MEKi is superior to monotherapy with a BRAFi. Further research should be done to explore the impact of BRAFi + MEKi treatment on the natural history of BRAFm NSCLC.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cohort Studies; Female; Humans; Imidazoles; Lung Neoplasms; Male; MAP Kinase Kinase Kinases; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Analysis; Vemurafenib

2019
Oncolytic HSV therapy increases trametinib access to brain tumors and sensitizes them in vivo.
    Neuro-oncology, 2019, 09-06, Volume: 21, Issue:9

    Hyperactivation of the RAS-RAF-MEK-ERK signaling pathway is exploited by glioma cells to promote their growth and evade apoptosis. MEK activation in tumor cells can increase replication of ICP34.5-deleted herpes simplex virus type 1 (HSV-1), but paradoxically its activation in tumor-associated macrophages promotes a pro-inflammatory signaling that can inhibit virus replication and propagation. Here we investigated the effect of blocking MEK signaling in conjunction with oncolytic HSV-1 (oHSV) for brain tumors.. Infected glioma cells co-cultured with microglia or macrophages treated with or without trametinib were used to test trametinib effect on macrophages/microglia. Enzyme-linked immunosorbent assay, western blotting, and flow cytometry were utilized to evaluate the effect of the combination therapy. Pharmacokinetic (PK) analysis of mouse plasma and brain tissue was used to evaluate trametinib delivery to the CNS. Intracranial human and mouse glioma-bearing immune deficient and immune competent mice were used to evaluate the antitumor efficacy.. Oncolytic HSV treatment rescued trametinib-mediated feedback reactivation of the mitogen-activated protein kinase signaling pathway in glioma. In vivo, PK analysis revealed enhanced blood-brain barrier penetration of trametinib after oHSV treatment. Treatment by trametinib, a MEK kinase inhibitor, led to a significant reduction in microglia- and macrophage-derived tumor necrosis factor alpha (TNFα) secretion in response to oHSV treatment and increased survival of glioma-bearing mice. Despite the reduced TNFα production observed in vivo, the combination treatment activated CD8+ T-cell mediated immunity and increased survival in a glioma-bearing immune-competent mouse model.. This study provides a rationale for combining oHSV with trametinib for the treatment of brain tumors.

    Topics: Animals; Blood-Brain Barrier; Brain Neoplasms; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Disease Models, Animal; Glioblastoma; Glioma; Herpesvirus 1, Human; Humans; Immunocompetence; Macrophages; Mice; Microglia; Mitogen-Activated Protein Kinase Kinases; Oncolytic Virotherapy; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; RAW 264.7 Cells; Survival Rate; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

2019
Sequential treatment failures in response to BRAF/MEK and immune checkpoint inhibitors mediated by MAP2K2 and B2M mutations in melanoma.
    Experimental and molecular pathology, 2019, Volume: 110

    Although the treatment of metastatic melanoma has been significantly improved by both anti-BRAF/MEK and checkpoint immunotherapies, resistance to these treatment modalities remains a substantial clinical problem. Multiple clinical studies are addressing the optimal sequencing of these agents in larger patient cohorts, but successful long-term individualized treatment will likely require the elucidation of resistance mechanisms from post-progression samples. Here, we describe a patient with BRAF-V600E-positive metastatic melanoma who was sequentially treated with BRAF/MEK inhibitors (dabrafenib/trametinib) and checkpoint inhibitor immunotherapy (nivolumab, followed by pembrolizumab). After the emergence of resistance, whole exome sequencing was performed, implicating MAP2K2 and B2M mutations in loss of response to anti-BRAF/MEK and anti-PD1 therapies, respectively.

    Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Humans; Imidazoles; Male; MAP Kinase Kinase 2; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Nivolumab; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Failure

2019
Severe gastrointestinal toxicity of MEK inhibitors.
    Melanoma research, 2019, Volume: 29, Issue:5

    Gastrointestinal toxicities of MEK inhibitors in melanoma patients are frequent. In clinical trials, the most common digestive adverse events were nausea, vomiting, and diarrhoea. However, severe toxicities such as colitis and gastrointestinal perforation, some with fatal outcomes, have been reported. These rare but severe adverse events are not well described. We performed a retrospective analysis of all patients with stage IV and unresectable stage III melanoma treated with a MEK inhibitors at Saint-Louis Hospital, Paris, between 1 August 2013 and 15 October 2018. Among 119 patients exposed to MEK inhibitors, 78 were treated with trametinib, 19 with cobimetinib, four with binimetinib, and 18 patients with two different MEK inhibitors at separate times. All grade digestive adverse events were observed in 39 (32.7%) patients. Grade 3 and 4 adverse events occurred in 6 (5%) patients: 2 (1.7%) developed perforations, 3 (2.5%) had colitis and 1 (0.8%) had grade 4 diarrhoea. These adverse events were all reversible following a permanent discontinuation of the MEK inhibitors, or a temporary interruption followed by resumption at a dose lower than conventional posology. There were no fatal outcomes; however one patient had a permanent ileostomy. The mechanism underlying these toxicities is not well known. Clinicians should be aware of such toxicities.

    Topics: Adult; Aged; Antineoplastic Agents; Azetidines; Benzimidazoles; Databases, Factual; Enzyme Inhibitors; Female; Gastrointestinal Tract; Humans; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Piperidines; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome

2019
Expression Signatures of Cisplatin- and Trametinib-Treated Early-Stage Medaka Melanomas.
    G3 (Bethesda, Md.), 2019, 07-09, Volume: 9, Issue:7

    Small aquarium fish models provide useful systems not only for a better understanding of the molecular basis of many human diseases, but also for first-line screening to identify new drug candidates. For testing new chemical substances, current strategies mostly rely on easy to perform and efficient embryonic screens. Cancer, however, is a disease that develops mainly during juvenile and adult stage. Long-term treatment and the challenge to monitor changes in tumor phenotype make testing of large chemical libraries in juvenile and adult animals cost prohibitive. We hypothesized that changes in the gene expression profile should occur early during anti-tumor treatment, and the disease-associated transcriptional change should provide a reliable readout that can be utilized to evaluate drug-induced effects. For the current study, we used a previously established medaka melanoma model. As proof of principle, we showed that exposure of melanoma developing fish to the drugs cisplatin or trametinib, known cancer therapies, for a period of seven days is sufficient to detect treatment-induced changes in gene expression. By examining whole body transcriptome responses we provide a novel route toward gene panels that recapitulate anti-tumor outcomes thus allowing a screening of thousands of drugs using a whole-body vertebrate model. Our results suggest that using disease-associated transcriptional change to screen therapeutic molecules in small fish model is viable and may be applied to pre-clinical research and development stages in new drug discovery.

    Topics: Animals; Animals, Genetically Modified; Biomarkers, Tumor; Cell Line, Tumor; Cisplatin; Computational Biology; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Oryzias; Pyridones; Pyrimidinones; Transcriptome; Xenograft Model Antitumor Assays

2019
Complete response for 36 months after BRAF and MEK inhibitor therapy for locally advanced gallbladder melanoma.
    Minerva gastroenterologica e dietologica, 2019, Volume: 65, Issue:3

    Topics: Antineoplastic Agents; Gallbladder Neoplasms; Humans; Imidazoles; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Middle Aged; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Time Factors; Treatment Outcome

2019
A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer.
    Science advances, 2019, Volume: 5, Issue:5

    Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Drosophila; Drug Administration Schedule; Drug Screening Assays, Antitumor; Female; Genes, ras; Genomics; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Precision Medicine; Pyridones; Pyrimidinones; Zoledronic Acid

2019
Trametinib Induces Neurofibroma Shrinkage and Enables Surgery.
    Neuropediatrics, 2019, Volume: 50, Issue:5

    Plexiform neurofibromas are congenital peripheral nerve sheath tumors characteristic of neurofibromatosis type 1 (NF1)-a frequent neurocutaneous disorder caused by mutations of the NF1 tumor suppressor gene. Since plexiform neurofibromas are a major cause of the burden of disease and may also progress to malignancy, many efforts have been undertaken to find a cure for these tumors. However, neither surgery nor medication has so far produced a breakthrough therapeutic success. Recently, a clinical phase I study reported significant shrinkage of plexiform neurofibromas following treatment with the MEK inhibitor selumetinib. Here, we report an 11-year-old NF1 patient with a large plexiform neurofibroma of the neck that had led to a sharp-angled kinking of the cervical spine and subsequent myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended, the vertebral column was inaccessible due to extensive tumor growth. In this situation, treatment with the MEK inhibitor trametinib was initiated which resulted in a 22% reduction in tumor volume after 6 months of therapy and finally enabled surgery. These data show that MEK inhibitors may not lead to complete disappearance of NF1-associated plexiform neurofibromas but can be an essential step in a multimodal therapeutic approach for these tumors. The course of our patient suggests that MEK inhibitors are likely to play a significant role in providing a cure for one of the most devastating manifestations of NF1.

    Topics: Antineoplastic Agents; Cervical Cord; Child; Female; Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Neurofibromin 1; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Treatment Outcome

2019
Combination treatment strategy for pancreatic cancer involving the novel HDAC inhibitor MPT0E028 with a MEK inhibitor beyond K-Ras status.
    Clinical epigenetics, 2019, 05-29, Volume: 11, Issue:1

    Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028.. The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo.. The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone.. The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Epigenesis, Genetic; ErbB Receptors; Flavonoids; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Male; Mice; Pancreatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2019
Dual inhibition of the PI3K and MAPK pathways enhances nab-paclitaxel/gemcitabine chemotherapy response in preclinical models of pancreatic cancer.
    Cancer letters, 2019, 09-10, Volume: 459

    Standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC), nab-paclitaxel (NPT) plus gemcitabine (Gem), has led to an average survival of 8.5 months. Presently, no therapeutics exist that effectively target the KRAS oncogene, activated in 95% of PDACs, but alternative strategies focus on inhibition of downstream effectors of KRAS signaling. Through combined inhibition of PI3K and MAPK signaling with MK-2206 (MK) and trametinib (Tra), enhancement of NPT + Gem response was evaluated. Median animal survival was significantly improved by the NPT + Gem combination (67% increase). Addition of MK-2206 or trametinib further increased median survival: NPT + Gem + MK (86%), NPT + Gem + Tra (105%), and NPT + Gem + MK + Tra (129%). In cell line-derived xenografts, the net tumor growth (in mm

    Topics: Albumins; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Drug Synergism; Female; Gemcitabine; Heterocyclic Compounds, 3-Ring; Humans; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Mice, SCID; Paclitaxel; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2019
Custo-utilidade de terapias-alvo comparadas à dacarbazina para o tratamento de primeira linha do melanoma avançado não-cirúrgico e metastático no Sistema Único de Saúde do Brazil.
    Value in health regional issues, 2019, Volume: 20

    To estimate the incremental cost-utility ratio (ICUR) of isolated and combined targeted therapy regimens compared to dacarbazine for first-line treatment of advanced and metastatic melanoma with BRAF V600 mutation.. A Markov model with three health states (no progression, progression and death), monthly duration cycle and 10-year time horizon was constructed to compare targeted therapy regimens (vemurafenib, dabrafenib, vemurafenib/cobimetinib and dabrafenib/trametinib) with dacarbazine chemotherapy under the Brazilian public health perspective. One-way and probabilistic sensitivity analyses were performed.. Mean cost was R$5662.50 ($1490.13) for dacarbazine, R$175 937.18 (46 299.26) for vemurafenib, R$167 461.70 ($44 068.87) for dabrafenib, R$425 901 ($112 079.21) for vemurafenib/cobimetinib and R$411 799.81 ($108 368.37) for dabrafenib/trametinib, whereas QALY was 0.91 for dacarbazine, 1.08 for vemurafenib, 1.12 for dabrafenib, 1.64 for vemurafenib/cobimetinib and 1.56 for dabrafenib/trametinib. The ICUR was estimated from R$572 165.76 ($150 569.94) to R$1 012 524.56 ($266 453.83) per patient, and the most impactful parameters were risk of progression and death, and treatment cost.. The incorporation of targeted therapies in the Brazilian public health system would produce an additional expenditure of at least 19 times the national GDP per capita to increase in one year the quality-adjusted survival of each patient with advanced/metastatic BRAF-mutant melanoma.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Brazil; Cost-Benefit Analysis; Dacarbazine; Drug Costs; Health Care Costs; Humans; Imidazoles; Melanoma; Oximes; Piperidines; Pyridones; Pyrimidinones; Vemurafenib

2019
Dynamics of neutrophil and C-reactive protein reflect the clinical course of pyrexia during combination therapy with dabrafenib and trametinib.
    The Journal of dermatology, 2019, Volume: 46, Issue:8

    Pyrexia is the most common adverse event in patients with melanoma or other solid organ malignancies that are treated with the combination of dabrafenib and trametinib (combi-DT). Given the expanded indication for combi-DT, management of pyrexia is a high priority. No previous case series has revealed which blood markers reflect the course of pyrexia and there is no consensus on the management strategy for pyrexia. The current case series study describes the utility of neutrophil count (NC), neutrophil ratio (NR) and C-reactive protein (CRP) in 11 patients with metastatic melanoma and BRAF V600 mutations who experienced pyrexia during combi-DT in our department. We also described the clinical course of pyrexia episodes that were managed with the concomitant use of oral prednisolone and immediate withdrawal of combi-DT. Consequently, the analysis of 37 pyrexia episodes in 11 patients showed that the differences in NC, NR and CRP at the onset of pyrexia were significantly different from those at pyretolysis (P = 0.01, 0.006 and 0.03, respectively). Additionally, in the 24 pyrexia episodes treated with the concomitant use of oral prednisolone and the immediate withdrawal of combi-DT, the mean duration of pyrexia and the mean time to restart combi-DT were 3 and 6 days, respectively. Therefore, the blood markers that reflect the course of pyrexia during combi-DT may be helpful for the appropriate management of pyrexia; also, our management strategy for pyrexia successfully reduced the duration of pyrexia and did not require a long-term drug holiday. Further large-scale studies are required to verify our results.

    Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; C-Reactive Protein; Feasibility Studies; Female; Fever; Humans; Imidazoles; Leukocyte Count; Male; Melanoma; Middle Aged; Neutrophils; Oximes; Prednisolone; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Time Factors; Treatment Outcome; Young Adult

2019
MCL1 inhibition enhances the therapeutic effect of MEK inhibitors in KRAS-mutant lung adenocarcinoma cells.
    Lung cancer (Amsterdam, Netherlands), 2019, Volume: 133

    MCL1 is an anti-apoptotic BCL2 family member that is highly expressed in various malignant tumors. However, little is known about the role of MCL1 in KRAS-mutant lung adenocarcinomas. In this study, we aimed to clarify whether MCL1 could be a therapeutic target in KRAS-mutant lung adenocarcinomas for which no effective molecular targeted drugs are available.. We examined to what extent MCL1 knockdown either alone or in combination with MEK inhibitor trametinib suppressed growth or induced apoptosis in the KRAS-mutant lung adenocarcinoma cell line H441 and EGFR-mutant lung adenocarcinoma cell line H1975. Furthermore, we investigated the therapeutic effects of dual inhibition of MCL1 and Bcl-xL, another anti-apoptotic BCL2 family member, in these two cell lines.. MCL1 knockdown alone did not induce apoptosis in H441 or H1975 cells. However, MCL1-depleted H441 and H1975 cells underwent apoptosis and decreased in number in the presence of trametinib. We also confirmed that combined therapy by MCL1 knockdown and trametinib almost completely suppressed the growth of H441 cells in vivo. Moreover, dual knockdown of MCL1 and Bcl-xL induced extensive apoptosis in H441 and H1975 cells.. These findings suggest that combined treatments of MCL1 knockdown and trametinib or dual inhibition of MCL1 and Bcl-xL would be effective therapies for lung adenocarcinomas including the KRAS-mutant subtype.

    Topics: Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; bcl-X Protein; Cell Line, Tumor; Cell Proliferation; Female; Gene Knockdown Techniques; Genetic Therapy; Lung Neoplasms; Mice; Mice, Nude; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2019
Empiric Therapy with BRAF and MEK Inhibitors in Metastatic Melanoma.
    The oncologist, 2019, Volume: 24, Issue:11

    BRAF and MEK inhibitors are highly active in the setting of

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Melanoma; Molecular Targeted Therapy; Neoplasm Metastasis; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2019
HDAC Inhibition Enhances the
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2019, 09-15, Volume: 25, Issue:18

    The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. This study has used multiomics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance.. Together, our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in advanced uveal melanoma.

    Topics: Animals; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Disease Progression; Drug Resistance, Neoplasm; Drug Synergism; Histone Deacetylase Inhibitors; Humans; MAP Kinase Signaling System; Melanoma; Mice; Panobinostat; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proteome; Proteomics; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Receptor Tyrosine Kinase-like Orphan Receptors; Receptor, IGF Type 1; Receptors, G-Protein-Coupled; Signal Transduction; Transcription Factors; Uveal Neoplasms; Xenograft Model Antitumor Assays

2019
Conjunctival Melanoma Targeted Therapy: MAPK and PI3K/mTOR Pathways Inhibition.
    Investigative ophthalmology & visual science, 2019, 06-03, Volume: 60, Issue:7

    To analyze the activity of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinases/mechanistic target of rapamycin (PI3K/mTOR) pathways in benign and malignant conjunctival melanocytic proliferations and explore whether specific inhibitors can suppress growth of conjunctival melanoma (CJM) cells.. The presence of a BRAF V600E mutation and activation of ERK, MEK, S6, and AKT were assessed with immunohistochemistry in 35 conjunctival nevi and 31 melanomas. Three CJM cell lines were used: CRMM1, carrying the BRAF V600E mutation; CRMM2, harboring the NRAS Q61L mutation; and T1527A, with a BRAF G466E mutation. WST-1 assays were performed with a BRAF inhibitor (vemurafenib), two MEK inhibitors (trametinib, selumetinib), a PI3K inhibitor (pictilisib), and a dual PI3K/mTOR inhibitor (dactolisib). The phosphorylation of ERK, MEK, and S6 were tested with western blots and apoptosis with cleaved caspase-3 immunostaining.. A BRAF V600E mutation was detected in 42.6% of nevi and in 35.5% of CJM. MEK and ERK activation were higher in CJM, occurring in 62.9% and 45.7% of the nevi and 90.3% and 96.8% of the CJM, respectively. There was also a significant increase in S6 activation in CJM (90.3%) compared with the nevi (20%). CRMM1 was sensitive to trametinib and the PI3K inhibitors but only marginally to vemurafenib. CRMM2 was moderately sensitive to pictilisib, whereas T1527A was resistant to all drugs tested.. The MAPK pathway activity in CJM is increased, not only as a consequence of the BRAF V600E mutation. Targeted therapy may be useful for patients with CJM, especially those with activating BRAF mutations, whereas NRAS-mutated melanomas are relatively resistant.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzimidazoles; Blotting, Western; Conjunctival Neoplasms; Female; Fluorescent Antibody Technique, Indirect; Humans; Imidazoles; Indazoles; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quinolines; Sulfonamides; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

2019
Dabrafenib Plus Trametinib for BRAF V600E-Mutant Non-small Cell Lung Cancer: A Patient Case Report.
    Clinical drug investigation, 2019, Volume: 39, Issue:10

    Dabrafenib plus trametinib is US Food and Drug Administration approved combination therapy for use in patients with BRAF V600E-mutant non-small cell lung cancer, but information on use outside of clinical trials is limited. We report the case of a 70-year-old Asian woman (never smoker) who was diagnosed with lung adenocarcinoma in May 2014. Testing at diagnosis was negative for programmed death ligand 1 or EGFR, ALK, and ROS1 alterations. She was started on carboplatin-pemetrexed-bevacizumab and maintenance bevacizumab but progressed in September 2015. Subsequently, she progressed on second-line nivolumab and third-line docetaxel. In March 2016, pleural fluid obtained at diagnosis tested positive for the BRAF V600E mutation and she received dabrafenib plus trametinib. She experienced rapid tumor shrinkage and symptom improvement and became able to participate in regular daily activities with no notable adverse events. In December 2016, she died from a hemorrhagic stroke considered unrelated to treatment. In this heavily pretreated patient with non-small cell lung cancer, dabrafenib plus trametinib elicited an excellent response.

    Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Female; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2019
ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor.
    Nature medicine, 2019, Volume: 25, Issue:7

    Topics: Adult; Animals; Child; Exome Sequencing; Female; HEK293 Cells; Humans; Lymphatic Abnormalities; Male; Mitogen-Activated Protein Kinase Kinases; Mutation; Proto-Oncogene Proteins A-raf; Pyridones; Pyrimidinones; Zebrafish

2019
Combined mTOR/MEK inhibition prevents proliferation and induces apoptosis in NF2-mutant tumors.
    European review for medical and pharmacological sciences, 2019, Volume: 23, Issue:13

    Merlin is encoded by Neurofibromatosis type 2 gene (NF-2), a tumor suppressor gene, which causes some multiple tumors forming disease of the nervous system in case of function loss. Bioinformatics analysis suggested that patients with NF-2 mutation had a worse prognosis, while it was associated with PI3K/mTOR activation, implying abnormal apoptosis in NF-2 mutation related tumors. Hence, we supposed that the inhibitors of PI3K/mTOR pathway might play a role in suppressing the tumor proliferation.. Two representative NF-2 mutation tumor model of NCI-H2452 and HEI193 cell lines were adopted, while two PI3K/mTOR pathway inhibitors Trametinib and Vistusertib were chosen to study the proliferation and apoptosis of the tumor cells.. CCK8 cell counting experiment showed that both Trametinib and Vistusertib could inhibit the proliferation of NCI-H2452 cell in vitro, while the combination of Trametinib and Vistusertib was more significant. Flow cytometry results showed that both Trametinib and Vistusertib could enhance apoptosis of NCI-H2452 cell in vitro, while the combination of Trametinib and Vistusertib was more significant. Similar results were also achieved for HEI193 cell lines. In vivo tumorigenicity experiments demonstrated that the tumor volume and weight were significantly decreased by both Trametinib and Vistusertib, while their combination had the most significant effect. Western blot results demonstrated that both Trametinib and Vistusertib could inhibit PI3K/mTOR /MEK pathway and enhance the expression of merlin.. We found that PI3K/mTOR inhibitor could decrease the proliferation of NF-2 mutation tumor cell lines by enhancing apoptosis, while the combination of two drugs might have a better effect.

    Topics: Antineoplastic Agents; Apoptosis; Benzamides; Cell Proliferation; Cells, Cultured; Computational Biology; Drug Screening Assays, Antitumor; Humans; Mesothelioma; Morpholines; Mutation; Neurofibromin 2; Phosphatidylinositol 3-Kinase; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Pyrimidinones; TOR Serine-Threonine Kinases

2019
Complete Surgical Resection Following Neoadjuvant Dabrafenib Plus Trametinib in
    Thyroid : official journal of the American Thyroid Association, 2019, Volume: 29, Issue:8

    Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Disease-Free Survival; Female; Humans; Imidazoles; Male; Middle Aged; Mutation; Neck Dissection; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Thyroidectomy

2019
Antitumor immune response during glioma virotherapy.
    Neuro-oncology, 2019, 09-06, Volume: 21, Issue:9

    Topics: Brain Neoplasms; Glioma; Humans; Oncolytic Virotherapy; Pyridones; Pyrimidinones

2019
Global view of the RAF-MEK-ERK module and its immediate downstream effectors.
    Scientific reports, 2019, 07-26, Volume: 9, Issue:1

    Small molecule inhibitors of BRAF and MEK have proven effective at inhibiting tumor growth in melanoma patients, however this efficacy is limited due to the almost universal development of drug resistance. To provide advanced insight into the signaling responses that occur following kinase inhibition we have performed quantitative (phospho)-proteomics of human melanoma cells treated with either dabrafenib, a BRAF inhibitor; trametinib, a MEK inhibitor or SCH772984, an ERK inhibitor. Over nine experiments we identified 7827 class I phosphorylation sites on 4960 proteins. This included 54 phosphorylation sites that were significantly down-modulated after exposure to all three inhibitors, 34 of which have not been previously reported. Functional analysis of these novel ERK targets identified roles for them in GTPase activity and regulation, apoptosis and cell-cell adhesion. Comparison of the results presented here with previously reported phosphorylation sites downstream of ERK showed a limited degree of overlap suggesting that ERK signaling responses may be highly cell line and cue specific. In addition we identified 26 phosphorylation sites that were only responsive to dabrafenib. We provide further orthogonal experimental evidence for 3 of these sites in human embryonic kidney cells over-expressing BRAF as well as further computational insights using KinomeXplorer. The validated phosphorylation sites were found to be involved in actin regulation, which has been proposed as a novel mechanism for inhibiting resistance development. These results would suggest that the linearity of the BRAF-MEK-ERK module is at least context dependent.

    Topics: Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Humans; Imidazoles; Indazoles; MAP Kinase Signaling System; Melanoma; Mitogen-Activated Protein Kinase Kinases; Oximes; Phosphorylation; Piperazines; Proteome; Proteomics; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2019
Mek Inhibitor Reverses Hypertrophic Cardiomyopathy in RIT1 Mutated Noonan Syndrome: For the first time, hypertrophic cardiomyopathy was reversed in Noonan syndrome associated with a RIT1 mutation.
    American journal of medical genetics. Part A, 2019, Volume: 179, Issue:8

    Topics: Anti-Arrhythmia Agents; Antineoplastic Agents; Cardiomyopathy, Hypertrophic; Cardiovascular Agents; Drug Repositioning; Echocardiography; Gene Expression Regulation; Heart Valves; Heterozygote; Humans; Infant; MAP Kinase Kinase 1; Mutation; Natriuretic Peptide, Brain; Noonan Syndrome; Peptide Fragments; Propranolol; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; ras Proteins; Signal Transduction; Treatment Outcome

2019
Inhibition of the ERK1/2-mTORC1 axis ameliorates proteinuria and the fibrogenic action of transforming growth factor-β in Adriamycin-induced glomerulosclerosis.
    Kidney international, 2019, Volume: 96, Issue:4

    Transforming growth factor-β (TGF-β) plays crucial roles in the development of focal segmental glomerulosclerosis, but key molecular pathways remain unknown. Here, we identified the regulation of mammalian target of rapamycin complex1 (mTORC1) by TGF-β via ERK1/2 in the Adriamycin-induced murine model of focal segmental glomerulosclerosis. Adriamycin administration elicited early activation of TGF-β-ERK1/2-mTORC1 in podocytes, which persisted at later stages of albuminuria and glomerulosclerosis. Phosphorylation of the TGF-β receptor-I (TGF-βRI), Smad3, ERK1/2 and ribosomal protein S6 were evident in the glomeruli of adriamycin-treated mice. Targeting TGFβ-RI and mTORC1 with pharmacological inhibitors suppressed TGF-β signaling in glomeruli and significantly reduced albuminuria, glomerulosclerosis, protein levels of collagen 4α3, plasminogen activator inhibitor-1, and vimentin and restored mRNA levels of podocyte markers. Low dose US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor trametinib/GSK1120212 blunted TGF-β1-induced mTORC1 activation in podocytes, ameliorated up-regulation of TGF-β, plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, fibronectin and α-smooth muscle actin and prevented albuminuria and glomerulosclerosis with improved serum albumin. In cultured podocytes, this pathway was found to be associated with translation of fibrogenic collagen 4α3 and plasminogen activator inhibitor-1, without influencing their transcription. Notably, rapamycin suppressed upstream p-TGF-βRI, p-Smad3 and p-ERK1/2, and trametinib down-regulated upstream p-Smad3 in ex vivo and in vivo studies, indicating that harmful paracrine signaling among glomerular cells amplified the TGF-β-ERK1/2-mTORC1 axis by forming a positive feedback loop. Thus, an accentuated TGF-β-ERK1/2-mTORC1 pathway is suggested as a central upstream mediator to develop proteinuria and glomerulosclerosis. Hence, preventing activation of this vicious loop by trametinib may offer a new therapeutic strategy for glomerular disease treatment.

    Topics: Animals; Cell Line; Disease Models, Animal; Doxorubicin; Drug Evaluation, Preclinical; Glomerulosclerosis, Focal Segmental; Humans; Kidney Glomerulus; Male; MAP Kinase Signaling System; Mechanistic Target of Rapamycin Complex 1; Mice; Phosphorylation; Proteinuria; Pyridones; Pyrimidinones; Rats; Transforming Growth Factor beta

2019
A Network Meta-Analysis of Short and Long-Term Efficacy of Targeted Therapy With Single or Double-Drug Regimens in the Treatment of Stage III/IV Malignant Melanoma Based on 16 Randomized Controlled Trials.
    Journal of cellular biochemistry, 2018, Volume: 119, Issue:1

    For the treatment of stage III/IV malignant melanoma (MM), a network meta-analysis (NMA) was conducted to compare the short and long-term efficacy of targeted therapy with single or double-drug regimens. All conducted randomized controlled trials (RCTs) searched from PubMed and Cochrane Library were included in the study for direct and indirect comparison for MM. The odds ratio (OR) and surface under the cumulative ranking curves (SUCRA) value of the targeted therapy with single or double-drug regimens for treatment of stage III/IV MM were also analyzed. To group the treatments according to their similarity with regards to both outcomes, cluster analyses were performed. Ultimately, 16 RCTs were incorporated for this NMA. The NMA revealed that the overall response rate (ORR) values of single-drug regimens (Vemurafenib [Vem], Dabrafenib [Dab], and Nivolumab [Niv]) were higher than those of Dacarbazine (Dac). Also the ORR values of double-drug regimens (Dab + Trametinib [Dab + Tra], Niv + Ipilimumab [Niv + Ipi], and Vem + Cobimetinib [Vem + Cob]) were moderately higher than those of Dac. The results of the SUCRA showed that short-term efficacy of single-drug regimens (Vem and Dab) were better, while the short-term efficacy of double-drug regimens (Dab + Tra and Vem + Cob) were relatively better. It was determined that Vem, Dab, and Niv might be the best choice in evaluating the treatment of stage III/IV MM among different single-drug targeted therapy regimens, while Dab + Tra, Niv + Ipi, and Vem + Cob might have better short-term efficacy among different double-drug targeted therapy regimens. J. Cell. Biochem. 119: 640-649, 2018. © 2017 Wiley Periodicals, Inc.

    Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Dacarbazine; Humans; Imidazoles; Indoles; Ipilimumab; Melanoma; Molecular Targeted Therapy; Neoplasm Staging; Network Meta-Analysis; Nivolumab; Odds Ratio; Oximes; Piperidines; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Sulfonamides; Survival Analysis; Treatment Outcome; Vemurafenib

2018
Acute heart failure as a result of granulomatous myocarditis: case report on a patient with metastatic melanoma treated with dabrafenib and trametinib.
    Journal of the European Academy of Dermatology and Venereology : JEADV, 2018, Volume: 32, Issue:1

    Topics: Acute Disease; Adult; Antineoplastic Agents; Granuloma; Heart Failure; Humans; Imidazoles; Lymphatic Metastasis; Male; Melanoma; Myocarditis; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

2018
Acanthoma planoepitheliale hyperkeratoticum, lesions associated with BRAF inhibitor in metastatic melanoma.
    Journal of the European Academy of Dermatology and Venereology : JEADV, 2018, Volume: 32, Issue:2

    Topics: Acanthoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

2018
Trametinib for the treatment of IGHV4-34, MAP2K1-mutant variant hairy cell leukemia.
    Leukemia & lymphoma, 2018, Volume: 59, Issue:4

    Topics: Genes, Immunoglobulin Heavy Chain; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Leukemia, Hairy Cell; Male; MAP Kinase Kinase 1; Middle Aged; Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Treatment Outcome

2018
ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor BKM120 in head and neck squamous cell carcinoma.
    Oncogene, 2018, 01-18, Volume: 37, Issue:3

    Hyperactivation of phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in head and neck squamous cell carcinoma (HNSCC). However, clinical outcomes of targeting the PI3K pathway have been underwhelming. In present study, we investigated the resistant mechanisms and potential combination therapeutic strategy to overcome adaptive resistance to PI3K inhibitor in HNSCC. Treatment of NVP-BKM120, a pan-PI3K inhibitor, led to upregulation of interleukin-6 (IL-6) and subsequent activation of either extracellular signal-regulated kinase (ERK) or signal transducers and activators of transcription 3 (STAT3), causing modest antitumor effects on the growth of HNSCC cells. Blockade of autocrine IL-6 signaling with siRNA or neutralizing antibody for IL-6 receptor (IL-6R) completely abolished NVP-BKM120-induced activation of ERK and STAT3 as well as expression of c-Myc oncogene, which resulted in enhanced sensitivity to NVP-BKM120. Moreover, when compared with a pharmacologic inhibitor or silencing of STAT3, trametinib, a MEK inhibitor, in combination with NVP-BKM120 yielded more potent anti-proliferative effects by inhibiting S phase transition, arresting cells at G0/G1 phase, and downregulating IL-6 and c-Myc expression. Furthermore, as compared with either agent alone, combination of NVP-BKM120 with trametinib or tocilizumab, a humanized anti-IL-6R antibody, significantly suppressed tumor growth in NVP-BKM120-resistant patient-derived tumor xenograft (PDTX) models, which was also confirmed in PDTX-derived cell lines. Collectively, these results suggested that IL-6/ERK signaling is closely involved in adaptive resistance of NVP-BKM120 in HNSCC cells, providing a rationale for a novel combination therapy to overcome resistance to PI3K inhibitors.

    Topics: Aminopyridines; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Autocrine Communication; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Female; Head and Neck Neoplasms; Humans; Interleukin-6; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptors, Interleukin-6; RNA, Small Interfering; Squamous Cell Carcinoma of Head and Neck; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

2018
Severe erythema exudative multiforme developing from advanced melanoma treated with dabrafenib and trametinib followed by nivolumab.
    The Journal of dermatology, 2018, Volume: 45, Issue:2

    Topics: Administration, Oral; Adult; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Drug Eruptions; Erythema Multiforme; Female; Glucocorticoids; Humans; Imidazoles; Melanoma; Neoplasm Staging; Nivolumab; Oximes; Pyridones; Pyrimidinones; Severity of Illness Index; Skin; Skin Neoplasms

2018
Dropped-head syndrome in a patient under treatment with the MEK inhibitor trametinib for NRAS-mutated metastatic melanoma.
    Clinical and experimental dermatology, 2018, Volume: 43, Issue:2

    Topics: Head; Humans; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Muscle Weakness; Neck Muscles; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2018
Response to MEK inhibition with trametinib and tyrosine kinase inhibition with imatinib in multifocal histiocytic sarcoma.
    Haematologica, 2018, Volume: 103, Issue:1

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biopsy; Combined Modality Therapy; Histiocytic Sarcoma; Humans; Imatinib Mesylate; Immunohistochemistry; Immunophenotyping; Male; Molecular Targeted Therapy; Positron Emission Tomography Computed Tomography; Pyridones; Pyrimidinones; Retreatment; Symptom Assessment; Treatment Outcome

2018
Real-World Experience with Targeted Therapy for the Treatment of Anaplastic Thyroid Carcinoma.
    Thyroid : official journal of the American Thyroid Association, 2018, Volume: 28, Issue:1

    Patients with anaplastic thyroid cancer (ATC) have a dismal prognosis, despite systemic cytotoxic chemotherapy. The objective of this study was to investigate the efficacy and safety of targeted therapy in ATC patients when used outside of a clinical trial.. This is a retrospective review from April 2015 to May 2016 at a single academic institution where 16 ATC patients receiving targeted therapy outside of a clinical trial were studied. Ten patients (eight BRAF wild type and two BRAF. The majority of patients (63%) were men, and all had distant metastases or radiation-resistant primary disease at the time of treatment. In the entire cohort, 6/16 (38%) had a partial response, 6/16 (38%) had stable disease, and 2/16 (12%) had progressive disease. Two (12%) patients died before restaging. Median follow-up time was 11.8 months. Median progression-free survival was 3.7 months [confidence interval 1.8-7.6] in the entire cohort, 2.7 months for lenvatinib, and 5.2 months for dabrafenib plus trametinib. Median OS was 6.3 months [confidence interval 1.8-7.6] for the entire cohort, 3.9 months for lenvatinib, and 9.3 months for dabrafenib plus trametinib. Adverse events were as expected and manageable.. Targeted therapies, lenvatinib, and dabrafenib plus trametinib (for BRAF

    Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Male; Middle Aged; Mutation; Oximes; Phenylurea Compounds; Prognosis; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Quinolines; Retrospective Studies; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome

2018
BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy.
    Pigment cell & melanoma research, 2018, Volume: 31, Issue:3

    BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAF

    Topics: Adult; Amino Acid Substitution; Base Sequence; Drug Resistance, Neoplasm; Female; Humans; Imidazoles; MAP Kinase Signaling System; Melanoma; Mutation, Missense; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sequence Deletion

2018
Acute intraventricular conduction disorder due to combination therapy with dabrafenib and trametinib for metastatic melanoma: Case report.
    The Journal of dermatology, 2018, Volume: 45, Issue:5

    Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cardiac Conduction System Disease; Electrocardiography; Female; Heart Conduction System; Heart Ventricles; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

2018
MAPK inhibitors induce serine peptidase inhibitor Kazal type 1 (SPINK1) secretion in BRAF V600E-mutant colorectal adenocarcinoma.
    Molecular oncology, 2018, Volume: 12, Issue:2

    The mitogen-activated protein kinase (MAPK) pathway plays a central role in colorectal cancers (CRC). In particular, BRAF V600E-mutant tumors, which represent around 10% of CRCs, are refractory to current therapies. Overexpression and secretion of serine peptidase inhibitor Kazal type 1 (SPINK1) are observed in around 50% of CRCs, and its serum level can be used as a biomarker for poor prognosis. Utilizing a recently developed extendable blocking probe assay, we analyzed the BRAF mutation status in a CRC patient cohort (N = 571) using tissue-derived RNA as the starting material. From the same RNA samples, we measured the relative SPINK1 expression levels using a quantitative real-time PCR method. Expression of mutant BRAF V600E correlated with poor prognosis, as did low expression of SPINK1 mRNA. Further, BRAF V600E correlated negatively with SPINK1 levels. In order to investigate the effect of MAPK pathway-targeted therapies on SPINK1 secretion, we conducted in vitro studies using both wild-type and V600E CRC cell lines. BRAF inhibitor vemurafenib, and subsequent MAPK pathway inhibitors trametinib and SCH772984, significantly increased SPINK1 secretion in V600E CRC cell lines Colo205 and HT-29 with a concomitant decrease in trypsin-1 and -2 secretion. Notably, no SPINK1 increase or trypsin-1 decrease was observed in BRAF wild-type CRC cell line Caco-2 in response to MAPK pathway inhibitors. In further mechanistic studies, we observed that only trametinib was able to diminish completely both MEK and ERK phosphorylation in the V600E CRC cells. Furthermore, the key regulator of integrated stress response, activating transcription factor 4 (ATF-4), was downregulated both at mRNA and at protein level in response to trametinib treatment. In conclusion, these data suggest that sustained inhibition of not only MAPK pathway activation, but also ATF-4 and trypsin, might be beneficial in the therapy of BRAF V600E-mutant CRC and that SPINK1 levels may serve as an indicator of therapy response.

    Topics: Activating Transcription Factor 4; Adenocarcinoma; Aged; Caco-2 Cells; Cell Line, Tumor; Cohort Studies; Colorectal Neoplasms; Female; HT29 Cells; Humans; Indazoles; Male; Middle Aged; Mitogen-Activated Protein Kinases; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Trypsin Inhibitor, Kazal Pancreatic

2018
Trametinib suppresses HIV-1 replication by interfering with the disassembly of human immunodeficiency virus type 1 capsid core.
    Biochemical and biophysical research communications, 2018, 01-08, Volume: 495, Issue:2

    Topics: Capsid; Dose-Response Relationship, Drug; Enzyme Activation; HIV-1; Mitogen-Activated Protein Kinase 1; Phosphorylation; Pyridones; Pyrimidinones; Virus Replication

2018
Sustained Response to Targeted Therapy in a Patient With Disseminated Anaplastic Pleomorphic Xanthoastrocytoma.
    Journal of pediatric hematology/oncology, 2018, Volume: 40, Issue:6

    Pleomorphic xanthoastrocytoma is a rare brain tumor with unique high frequency of BRAF V600E mutation which is plausible for targeted therapy. The anaplastic variant has generally worse prognosis. We present an adolescent patient with a disseminated relapse of anaplastic pleomorphic xanthoastrocytoma following surgery, radiotherapy, and chemotherapy. She had a dramatic and prolonged response to a BRAF inhibitor (Dabrafinib) and later to addition of a MEK inhibitor (Trametinib) on tumor progression. With minimal side effects and a good quality of life, the patient is alive more than 2 years after initiation of targeted therapy. This experience confirms the potential role of targeted treatments in high-grade BRAF-mutated brain tumors.

    Topics: Adolescent; Amino Acid Substitution; Astrocytoma; Brain Neoplasms; Female; Humans; Imidazoles; Mutation, Missense; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2018
Specificity of Phosphorylation Responses to Mitogen Activated Protein (MAP) Kinase Pathway Inhibitors in Melanoma Cells.
    Molecular & cellular proteomics : MCP, 2018, Volume: 17, Issue:4

    Topics: Cell Line, Tumor; Humans; Indazoles; Melanoma; Mitogen-Activated Protein Kinases; Phosphorylation; Piperazines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction

2018
Rapid Clinical and Radiographic Response With Combined Dabrafenib and Trametinib in Adults With
    Journal of the National Comprehensive Cancer Network : JNCCN, 2018, Volume: 16, Issue:1

    Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Child; Child, Preschool; Female; Glioma; Humans; Imidazoles; Infant; Magnetic Resonance Imaging; Male; Molecular Targeted Therapy; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiography; Treatment Outcome

2018
Dabrafenib and trametinib combination therapy safely performed in a patient with metastatic melanoma after severe liver toxicity due to vemurafenib.
    The Journal of dermatology, 2018, Volume: 45, Issue:6

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Female; Humans; Imidazoles; Liver Function Tests; Melanoma; Oximes; Pyridones; Pyrimidinones; Severity of Illness Index; Skin Neoplasms; Vemurafenib

2018
Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers.
    Oncogene, 2018, Volume: 37, Issue:13

    BRAF is one of the most frequently mutated genes across a number of different cancers, with the best-characterized mutation being V600E. Despite the successes of treating BRAF mutant V600E lung cancer with BRAF pathway inhibitors, treatment strategies targeting tumors with non-V600E mutations are yet to be established. We studied cellular signaling differences between lung cancers with different BRAF mutations and determined their sensitivities to BRAF pathway inhibitors. Here, we observed that MEK inhibition induced feedback activation of the receptor tyrosine kinase (RTK) EGFR, and in some cases the RTK FGFR, resulting in transient suppression of ERK phosphorylation in BRAF non-V600E, but not BRAF V600E, mutant cells. Furthermore, we found that both EGFR and FGFR activated the MEK/ERK pathway, despite the presence of BRAF non-V600E mutations with elevated kinase activity. Moreover, in BRAF non-V600E mutants with impaired kinase activities, EGFR had even greater control over the MEK/ERK pathway, essentially contributing completely to the tonic mitogen-activated protein kinase (MAPK) signal. Accordingly, the combination of MEK inhibitor with EGFR inhibitor was effective at shrinking tumors in mouse model of BRAF non-V600E mutant lung cancer. Furthermore, the results were recapitulated with a clinically relevant dual inhibitor of EGFR and RAF, BGB-283. Overall, although BRAF V600E mutant cells are sensitive to BRAF inhibition, non-V600E mutant cancer cells are reliant on RTKs for their MAPK activation and inhibiting both MEK and RTKs are necessary in these cancers. Our findings provide evidence of critical survival signals in BRAF non-V600E mutant cancers, which could pave the way for effective treatment of these cancers.

    Topics: Amino Acid Substitution; Animals; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Glutamic Acid; HT29 Cells; Humans; Lung Neoplasms; Male; MAP Kinase Signaling System; Mice; Mice, Nude; Mutant Proteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Receptor Protein-Tyrosine Kinases; Signal Transduction; Tumor Cells, Cultured; Valine; Xenograft Model Antitumor Assays

2018
Clinical and radiological response of BRAF inhibition and MEK inhibition in patients with brain metastases from BRAF-mutated melanoma.
    Melanoma research, 2018, Volume: 28, Issue:2

    Patients with brain metastases (BM) from melanoma have an overall survival (OS) of 2-6 months after whole-brain radiotherapy. Targeted therapy (TT) is an effective treatment for BRAF-mutated metastatic melanoma. Moreover, recent studies indicate intracranial responses of TT in patients with BM. We analyzed 146 patients with BM from BRAF-mutated melanoma treated with vemurafenib, dabrafenib, or dabrafenib+trametinib between 2010 and 2016. We determined clinical and radiological response, progression-free survival (PFS), and OS. Median OS of patients treated with dabrafenib+trametinib was 11.2 months [n=30; 95% confidence interval (CI): 6.8-15.7], 8.8 months for dabrafenib alone (n=31; 95% CI: 3.9-13.7), and 5.7 months for vemurafenib (n=85; 95% CI: 4.6-6.8). A significantly longer OS was observed in the dabrafenib+trametinib group than in the vemurafenib group (hazard ratio for death, 0.52; 95% CI: 0.30-0.89; P=0.02). Median intracranial PFS of all patients was 4.1 months. Median intracranial PFS for patients treated with dabrafenib+trametinib was 5.8 months (95% CI: 3.2-8.5), 5.7 months (95% CI: 3.0-8.4) for dabrafenib, and 3.6 months (95% CI: 3.5-3.8) for vemurafenib (P=0.54). A total of 63 (43%) patients had symptomatic BM. Intracranial disease control rate at 8 weeks in these patients was 65 versus 70% extracranially. Neurological symptoms improved in 46% of patients with symptomatic BM, whereas in 21%, they remained stable. Median OS in patients with BM from BRAF-mutated melanoma treated with dabrafenib+trametinib was significantly longer than for vemurafenib. Improvement of neurological symptoms was seen in almost half of the patients with symptomatic BM treated with TT.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Treatment Outcome; Vemurafenib; Young Adult

2018
Success of rechallenging dabrafenib and trametinib combination therapy after trametinib-induced rhabdomyolysis: a case report.
    Melanoma research, 2018, Volume: 28, Issue:2

    The mitogen-activated protein kinase pathway regulates cell growth and differentiation and is activated by BRAF mutations. BRAF mutations are present in about 40-50% of cutaneous melanomas. More than 90% of BRAF mutations are the V600E type. BRAF inhibitor (dabrafenib or vemurafenib) and MEK inhibitor (trametinib or cobimetinib) combination therapies are effective for BRAF-mutant advanced melanomas. A variety of side effects have been observed with combination therapy including pyrexia, fatigue, nausea, and vomiting. Rhabdomyolysis is one of the most severe adverse events, but it is very rare. Only two cases of rhabdomyolysis have been reported in clinical trials. A 41-year-old Japanese woman with cutaneous melanoma was started on a combination of dabrafenib and trametinib therapy after failure of immune checkpoint therapy. One month later, she complained of myalgia and fatigue and was shifted to our hospital. She was diagnosed with trametinib-induced rhabdomyolysis and showed improvement only with a high volume of fluid infusion. We stopped combination therapy, but there were no useful treatment options for her. After resuming dabrafenib, followed by trametinib, she did not have any problems. This is the first case of a patient with metastatic cutaneous melanoma who could recommence combination therapy after trametinib-associated rhabdomyolysis. We assume that not all patients experience recurrence of rhabdomyolysis in trametinib-induced rhabdomyolysis. As few cases have been reported, more information is needed. We have to evaluate safety carefully if rechallenging combination therapy.

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Rhabdomyolysis; Skin Neoplasms

2018
Neoadjuvant therapy in melanoma: the next step?
    The Lancet. Oncology, 2018, Volume: 19, Issue:2

    Topics: Humans; Imidazoles; Melanoma; Neoadjuvant Therapy; Oximes; Pyridones; Pyrimidinones; Standard of Care

2018
Pyoderma Gangrenosum Under Dabrafenib and Trametinib for Metastatic Melanoma.
    Acta dermato-venereologica, 2018, Apr-27, Volume: 98, Issue:5

    Topics: Aged; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Male; Melanoma; Methicillin-Resistant Staphylococcus aureus; Oximes; Protein Kinase Inhibitors; Pyoderma Gangrenosum; Pyridones; Pyrimidinones; Risk Factors; Skin Neoplasms; Staphylococcal Infections; Treatment Outcome

2018
Response to the BRAF/MEK inhibitors dabrafenib/trametinib in an adolescent with a BRAF V600E mutated anaplastic ganglioglioma intolerant to vemurafenib.
    Pediatric blood & cancer, 2018, Volume: 65, Issue:5

    Efficacy of BRAF V600E targeted therapies in brain tumors harboring the mutation has been shown in several case reports and is currently being studied in larger clinical trials. Monotherapy with vemurafenib has been associated with significant side effects, including rashes, papillomas, and squamous cell carcinomas. Here we describe an adolescent female with anaplastic ganglioglioma and significant skin reaction to vemurafenib with subsequent tumor response and tolerance to the BRAF/MEK inhibitor combination of dabrafenib and trametinib without recurrence of previous reaction.

    Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Drug Resistance, Neoplasm; Female; Ganglioglioma; Humans; Imidazoles; MAP Kinase Kinase 1; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Vemurafenib

2018
Trametinib inhibits
    Haematologica, 2018, Volume: 103, Issue:4

    Topics: Animals; Cell Line, Tumor; Gene Rearrangement; Heterografts; Histone-Lysine N-Methyltransferase; Humans; MAP Kinase Signaling System; Mice; Myeloid-Lymphoid Leukemia Protein; Phosphorylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyridones; Pyrimidinones; ras Proteins; Tumor Burden

2018
Case of deep vein thrombosis in a patient with advanced malignant melanoma treated with dabrafenib and trametinib.
    The Journal of dermatology, 2018, Volume: 45, Issue:7

    Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemotherapy, Adjuvant; Female; Fibrinolytic Agents; Humans; Imidazoles; Leg; Lymph Node Excision; Lymphatic Metastasis; Melanoma; Oximes; Pyridones; Pyrimidinones; Sentinel Lymph Node; Skin Neoplasms; Ultrasonography; Venous Thrombosis

2018
FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring
    The oncologist, 2018, Volume: 23, Issue:6

    On June 22, 2017, the Food and Drug Administration expanded indications for dabrafenib and trametinib to include treatment of patients with metastatic non-small cell lung cancer (NSCLC) harboring BRAF V600E mutations. Approval was based on results from an international, multicenter, multicohort, noncomparative, open-label trial, study BRF113928, which sequentially enrolled 93 patients who had received previous systemic treatment for advanced NSCLC (Cohort B,. The approvals of dabrafenib and trametinib, administered concurrently, provide a new regimen for the treatment of a rare subset of non-small cell lung cancer (NSCLC) and demonstrate how drugs active for treatment of

    Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Female; Humans; Imidazoles; Lung Neoplasms; Male; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

2018
EGFR-PI3K-PDK1 pathway regulates YAP signaling in hepatocellular carcinoma: the mechanism and its implications in targeted therapy.
    Cell death & disease, 2018, 02-15, Volume: 9, Issue:3

    The epidermal growth factor receptor (EGFR) pathway and Hippo signaling play an important role in the carcinogenesis of hepatocellular carcinoma (HCC). However, the crosstalk between these two pathways and its implications in targeted therapy remains unclear. We found that the activated EGFR signaling could bypass RhoA to promote the expression of YAP(Yes-associated protein), the core effector of the Hippo signaling, and its downstream target Cyr61. Further studies indicated that EGFR signaling mainly acted through the PI3K-PDK1 (Phosphoinositide 3-kinase-Phosphoinositide-dependent kinase-1) pathway to activate YAP, but not the AKT and MAPK pathways. While YAP knockdown hardly affected the EGFR signaling. In addition, EGF could promote the proliferation of HCC cells in a YAP-independent manner. Combined targeting of YAP and EGFR signaling by simvastatin and the EGFR signaling inhibitors, including the EGFR tyrosine kinase inhibitor (TKI) gefitinib, the RAF inhibitor sorafenib and the MEK inhibitor trametinib, presented strong synergistic cytotoxicities in HCC cells. Therefore, the EGFR-PI3K-PDK1 pathway could activate the YAP signaling, and the activated EGFR signaling could promote the HCC cell growth in a YAP-independent manner. Combined use of FDA-approved inhibitors to simultaneously target YAP and EGFR signaling presented several promising therapeutic approaches for HCC treatment.

    Topics: 3-Phosphoinositide-Dependent Protein Kinases; Adaptor Proteins, Signal Transducing; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Proliferation; ErbB Receptors; Gefitinib; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Molecular Targeted Therapy; Phosphatidylinositol 3-Kinase; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; Simvastatin; Sorafenib; Transcription Factors; YAP-Signaling Proteins

2018
Novel 3D Liquid Cell Culture Method for Anchorage-independent Cell Growth, Cell Imaging and Automated Drug Screening.
    Scientific reports, 2018, 02-26, Volume: 8, Issue:1

    Cells grown in three-dimensional (3D) cultures are more likely to have native cell-cell and cell-matrix interactions than in 2D cultures that impose mechanical constraints to cells. However, most 3D cultures utilise gel matrix which, while serving as a scaffold, limits application due to its solid and opaque nature and inconsistency in cell exposure to exogenous signals. In 3D culture without gel matrix, cells tend to adhere to each other and form clumps with necrotic zone at the centre, making them unsuitable for analyses. Here we report that addition of low-molecular-weight agar named LA717 to culture media allows cells to grow as dispersed clonal spheroids in 3D. LA717 maintains cells dispersed and settled to the bottom of the medium while keeping the medium clear with little additional viscosity, making it suitable for microscopic observation. Importantly, cancer spheroids formed in LA717-containing medium show higher sensitivity to anti-cancer drugs such as Trametinib and MK-2206 that are not as effective in 2D. Because of the small and consistent size of spheroids, cell viability and drug toxicity are readily detectable in automated imaging analysis. These results demonstrate that LA717 offers a novel 3D culture system with great in vivo reflection and practicality.

    Topics: A549 Cells; Antineoplastic Agents; Apoptosis; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Evaluation, Preclinical; HCT116 Cells; HeLa Cells; Hep G2 Cells; Heterocyclic Compounds, 3-Ring; Humans; Pyridones; Pyrimidinones; Real-Time Polymerase Chain Reaction; Spheroids, Cellular

2018
HLA-DRB1*04:05 in two cases of Vogt-Koyanagi-Harada disease-like uveitis developing from an advanced melanoma patient treated by sequential administration of nivolumab and dabrafenib/trametinib therapy.
    The Journal of dermatology, 2018, Volume: 45, Issue:6

    Although uveitis is reported as a rare adverse event (AE) associated with dabrafenib/trametinib therapy or nivolumab, the occurrence of severe uveitis is extremely rare. We describe two cases of Vogt-Koyanagi-Harada (VKH)-like uveitis developing after the sequential administration of nivolumab and dabrafenib/trametinib therapy. Interestingly, both cases had HLA-DRB1*04:05, which is strongly associated with VKH disease, and achieved biologically complete remission after the treatment for uveitis. Our cases suggest a possible correlation between VKH-like uveitis as an AE and the clinical outcomes of sequential administration of nivolumab and dabrafenib/trametinib therapy for the treatment of advanced melanoma.

    Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Choroid; Female; Glucocorticoids; HLA-DRB1 Chains; Humans; Imidazoles; Magnetic Resonance Imaging; Male; Melanoma; Nivolumab; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Uveomeningoencephalitic Syndrome; Visual Acuity

2018
Comment on "MEK inhibition with trametinib and tyrosine kinase inhibition with imatinib in multifocal histiocytic sarcoma".
    Haematologica, 2018, Volume: 103, Issue:3

    Topics: Histiocytic Sarcoma; Humans; Imatinib Mesylate; Protein-Tyrosine Kinases; Pyridones; Pyrimidinones

2018
A rare BRAF T599dup mutation conferring sensitivity to BRAF inhibitor in a patient with metastatic melanoma.
    The British journal of dermatology, 2018, Volume: 179, Issue:2

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; DNA Mutational Analysis; Humans; Imidazoles; Lymphatic Metastasis; Male; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2018
Copper Silicate Hollow Microspheres-Incorporated Scaffolds for Chemo-Photothermal Therapy of Melanoma and Tissue Healing.
    ACS nano, 2018, 03-27, Volume: 12, Issue:3

    The treatment of melanoma requires complete removal of tumor cells and simultaneous tissue regeneration of tumor-initiated cutaneous defects. Herein, copper silicate hollow microspheres (CSO HMSs)-incorporated bioactive scaffolds were designed for chemo-photothermal therapy of skin cancers and regeneration of skin tissue. CSO HMSs were synthesized with interior hollow and external nanoneedle microstructure, showing excellent drug-loading capacity and photothermal effects. With incorporation of drug-loaded CSO HMSs into the electrospun scaffolds, the composite scaffolds exhibited excellent photothermal effects and controlled NIR-triggered drug release, leading to distinctly synergistic chemo-photothermal therapy of skin cancer both in vitro and in vivo. Furthermore, such CSO HMSs-incorporated scaffolds could promote proliferation and attachment of normal skin cells and accelerate skin tissue healing in tumor-bearing and diabetic mice. Taken together, CSO HMSs-incorporated scaffolds may be used for complete eradication of the remaining tumor cells after surgery and simultaneous tissue healing, which offers an effective strategy for therapy and regeneration of tumor-initiated tissue defects.

    Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Copper; Drug Carriers; Drug Delivery Systems; Hyperthermia, Induced; Male; Melanoma; Mice, Inbred BALB C; Mice, Nude; Nanostructures; Phototherapy; Pyridones; Pyrimidinones; Silicates; Skin Neoplasms; Tissue Scaffolds

2018
Fatherhood during dabrafenib and trametinib therapy for metastatic melanoma.
    Acta oncologica (Stockholm, Sweden), 2018, Volume: 57, Issue:8

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Father-Child Relations; Fathers; Female; Fertility; Humans; Imidazoles; Infant, Newborn; Male; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Pregnancy; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Semen Analysis; Skin Neoplasms

2018
Quantification of the next-generation oral anti-tumor drugs dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib and two metabolites in human plasma by liquid chromatography-tandem mass spectrometry.
    Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 2018, Apr-15, Volume: 1083

    A sensitive and selective method of high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS) has been developed for the simultaneous quantification of six anticancer protein kinase inhibitors (PKIs), dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib, and two active metabolites (regorafenib-M2 and regorafenib-M5) in human plasma. Plasma protein precipitation with methanol enables the sample extraction of 100 μL aliquot of plasma. Analytes are detected by electrospray triple-stage quadrupole mass spectrometry and quantified using the calibration curves with stable isotope-labeled internal standards. The method was validated based on FDA recommendations, including assessment of extraction yield (74-104%), matrix effects, analytical recovery (94-104%) with low variability (<15%). The method is sensitive (lower limits of quantification within 1 to 200 ng/mL), accurate (intra- and inter-assay bias: -0.3% to +12.7%, and -3.2% to +6.3%, respectively) and precise (intra- and inter-assay CVs within 0.7-7.3% and 2.5-8.0%, respectively) over the clinically relevant concentration range (upper limits of quantification 500 to 100,000 ng/mL). This method is applied in our laboratory for both clinical research programs and routine therapeutic drug monitoring service of PKIs.

    Topics: Administration, Oral; Antineoplastic Agents; Azetidines; Child; Chromatography, High Pressure Liquid; Humans; Imidazoles; Indazoles; Indoles; Limit of Detection; Linear Models; Oximes; Phenylurea Compounds; Piperidines; Pyridines; Pyridones; Pyrimidines; Pyrimidinones; Reproducibility of Results; Sulfonamides; Tandem Mass Spectrometry; Vemurafenib

2018
ORAL DRUG THERAPY - IMPROVING SURVIVAL IN MALIGNANT MELANOMA.
    The Ulster medical journal, 2018, Volume: 87, Issue:1

    Topics: Administration, Oral; Antineoplastic Agents; Humans; Imidazoles; Melanoma; Neoplasm Metastasis; Neoplasm Staging; Oximes; Pyridones; Pyrimidinones; Survival Rate

2018
    Anticancer research, 2018, Volume: 38, Issue:4

    Advances in therapies targeting proteins and pathways affected by genetic alterations has raised the possibility of personalized cancer treatments.. The efficacy of targeting molecular aberrations was determined in the pancreatic ductal adenocarcinoma (PDAC) cell line, CAPAN2. Two mutations were targeted, KRAS (p.G12V) and ABL1 (p.G1060D), and cells were treated with regorafenib and trametinib, individually and in combination.. Exposure to either drug significantly increased cell death compared to the current standard of care, gemcitabine. Treatment with combinations of the drugs led to significant increases in cell death compared to either monotherapy. Strong additive/synergistic interactions were observed across a range of dosages and ratios, reducing dose requirements with potential clinical relevance.. The data obtained in this PDAC cell model: i) support the use of matched monotherapies; ii) indicate the effectiveness of matched combination therapies; and iii) provide potential proof-of-concept for precision medicine approach to cancer treatment.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Deoxycytidine; Drug Synergism; Gemcitabine; Humans; Pancreatic Neoplasms; Phenylurea Compounds; Piperazines; Protein Kinase Inhibitors; Pyridines; Pyridones; Pyrimidinones

2018
Steroid refractory dermatomyositis following combination dabrafenib and trametinib therapy.
    Rheumatology (Oxford, England), 2018, Aug-01, Volume: 57, Issue:8

    Topics: Aged, 80 and over; Antineoplastic Agents; Dermatomyositis; Drug Resistance; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Imidazoles; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2018
An Acquired NRAS Q61K Mutation in BRAF V600E-Mutant Lung Adenocarcinoma Resistant to Dabrafenib Plus Trametinib.
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2018, Volume: 13, Issue:8

    Topics: Adenocarcinoma of Lung; Drug Resistance, Neoplasm; Female; Humans; Imidazoles; Lung Neoplasms; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2018
BRAF Adds an Additional Piece of the Puzzle to Precision Oncology-Based Treatment Strategies in Lung Cancer.
    Archives of pathology & laboratory medicine, 2018, Volume: 142, Issue:7

    Topics: Amino Acid Substitution; Antineoplastic Agents; Drug Therapy, Combination; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Precision Medicine; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2018
Granulocyte colony-stimulating factor-producing melanoma treated with the combination of dabrafenib and trametinib.
    International journal of dermatology, 2018, Volume: 57, Issue:7

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Fatal Outcome; Granulocyte Colony-Stimulating Factor; Head and Neck Neoplasms; Humans; Imidazoles; Male; Melanoma; Oximes; Pyridones; Pyrimidinones; Scalp; Skin Neoplasms

2018
Survivin knockdown induces senescence in TTF‑1-expressing, KRAS-mutant lung adenocarcinomas.
    International journal of oncology, 2018, Volume: 53, Issue:1

    Survivin plays a key role in regulating the cell cycle and apoptosis, and is highly expressed in the majority of malignant tumors. However, little is known about the roles of survivin in KRAS-mutant lung adenocarcinomas. In the present study, we examined 28 KRAS-mutant lung adenocarcinoma tissues and two KRAS-mutant lung adenocarcinoma cell lines, H358 and H441, in order to elucidate the potential of survivin as a therapeutic target. We found that 19 (68%) of the 28 KRAS-mutant lung adenocarcinomas were differentiated tumors expressing thyroid transcription factor‑1 (TTF‑1) and E-cadherin. Patients with tumors immunohistochemically positive for survivin (n=18) had poorer outcomes than those with survivin-negative tumors (n=10). In the H358 and H441 cells, which expressed TTF‑1 and E-cadherin, survivin knockdown alone induced senescence, not apoptosis. However, in monolayer culture, the H358 cells and H441 cells in which survivin was silenced, underwent significant apoptosis following combined treatment with ABT-263, a Bcl‑2 inhibitor, and trametinib, a MEK inhibitor. Importantly, the triple combination of survivin knockdown with ABT-263 and trametinib treatment, clearly induced cell death in a three-dimensional cell culture model and in an in vivo tumor xenograft model. We also observed that the growth of the H358 and H441 cells was slightly, yet significantly suppressed in vitro when TTF‑1 was silenced. These findings collectively suggest that the triple combination of survivin knockdown with ABT-263 and trametinib treatment, may be a potential strategy for the treatment of KRAS-mutant lung adenocarcinoma. Furthermore, our findings indicate that the well‑differentiated type of KRAS-mutant lung tumors depends, at least in part, on TTF‑1 for growth.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Aniline Compounds; Cadherins; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Cellular Senescence; DNA-Binding Proteins; Female; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Male; MAP Kinase Kinase Kinase 1; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Sulfonamides; Survivin; Transcription Factors

2018
Characterising the phenotypic evolution of circulating tumour cells during treatment.
    Nature communications, 2018, 04-16, Volume: 9, Issue:1

    Real-time monitoring of cancer cells' phenotypic evolution during therapy can provide vital tumour biology information for treatment management. Circulating tumour cell (CTC) analysis has emerged as a useful monitoring tool, but its routine usage is restricted by either limited multiplexing capability or sensitivity. Here, we demonstrate the use of antibody-conjugated and Raman reporter-coated gold nanoparticles for simultaneous labelling and monitoring of multiple CTC surface markers (named as "cell signature"), without the need for isolating individual CTCs. We observe cell heterogeneity and phenotypic changes of melanoma cell lines during molecular targeted treatment. Furthermore, we follow the CTC signature changes of 10 stage-IV melanoma patients receiving immunological or molecular targeted therapies. Our technique maps the phenotypic evolution of patient CTCs sensitively and rapidly, and shows drug-resistant clones having different CTC signatures of potential clinical value. We believe our proposed method is of general interest in the CTC relevant research and translation fields.

    Topics: Antibodies, Neoplasm; Antineoplastic Agents; Biomarkers, Tumor; CD146 Antigen; Cell Line, Tumor; Cell Tracking; Gene Expression; Gold; Humans; Imidazoles; Immunoconjugates; Immunophenotyping; Melanoma; Metal Nanoparticles; Mitochondrial Proteins; Molecular Targeted Therapy; Neoplastic Cells, Circulating; Nerve Tissue Proteins; Oximes; Phenotype; Primary Cell Culture; Pyridones; Pyrimidinones; Receptor, ErbB-3; Receptors, Nerve Growth Factor; Skin Neoplasms; Spectrum Analysis, Raman; Staining and Labeling

2018
Histiocytoid Sweet's syndrome during combined therapy with BRAF and MEK inhibitors for metastatic melanoma.
    Melanoma research, 2018, Volume: 28, Issue:3

    Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sweet Syndrome

2018
Encephalocraniocutaneous Lipomatosis.
    Journal of pediatric hematology/oncology, 2018, Volume: 40, Issue:7

    A 5-year-old boy presented with worsening headaches for 3 months. On examination, he was found to have a hairless fatty tissue nevus of the scalp (nevus psiloliparus), subcutaneous soft tissue masses on the right side of his face, neck, mandible and right buttock and epibulbar dermoid of the right eye (choristoma) (). Magnetic resonance imaging revealed a large suprasellar mass, which was debulked and found to be a pilocytic astrocytoma. Testing was not performed for the BRAF/KIAA1549 fusion or BRAFV600E mutation. Seven years later, he was started on adjuvant chemotherapy for gradual tumor progression. Over the ensuing 3 years, he had further disease progression despite treatment with 3 frontline chemotherapy regimens: vinblastine, carboplatin/vincristine, and irinotecan/bevacizumab. Targeted sequencing of tissue from the right gluteal mass, revealed a mosaic activating FGFR1 c.1966A>G (p.Lys656Glu) mutation, absent in normal left gluteal tissue, confirming the diagnosis of encephalocraniocutaneous lipomatosis (ECCL), belonging to the family of RASopathies (including neurofibromatosis type I, Noonan syndrome, Costello syndrome), with constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, and an increased risk of developing neoplasms. He was started on trametinib, a MEK inhibitor, off-label, targeting the MAPK pathway downstream from FGFR1, with stable tumor size at last follow-up, after 6 months on therapy.

    Topics: Astrocytoma; Child, Preschool; Disease Progression; Eye Diseases; Humans; Lipomatosis; Magnetic Resonance Imaging; Male; Mitogen-Activated Protein Kinases; Neurocutaneous Syndromes; Pyridones; Pyrimidinones; Receptor, Fibroblast Growth Factor, Type 1; Treatment Outcome

2018
Response to Trametinib of a Pulmonary Langerhans Cell Histiocytosis Harboring a MAP2K1 Deletion.
    American journal of respiratory and critical care medicine, 2018, 09-01, Volume: 198, Issue:5

    Topics: Adolescent; Antineoplastic Agents; Histiocytosis, Langerhans-Cell; Humans; Lung; Male; MAP Kinase Kinase 1; Pyridones; Pyrimidinones; Tomography, X-Ray Computed; Treatment Outcome

2018
A modified gene trap approach for improved high-throughput cancer drug discovery.
    Oncogene, 2018, Volume: 37, Issue:31

    While advances in laboratory automation has dramatically increased throughout of compound screening efforts, development of robust cell-based assays in relevant disease models remain resource-intensive and time-consuming, presenting a bottleneck to drug discovery campaigns. To address this issue, we present a modified gene trap approach to efficiently generate pathway-specific reporters that result in a robust "on" signal when the pathway of interest is inhibited. In this proof-of-concept study, we used vemurafenib and trametinib to identify traps that specifically detect inhibition of the mitogen-activated protein kinase (MAPK) pathway in a model of BRAFV600E driven human malignant melanoma. We demonstrate that insertion of our trap into particular loci results in remarkably specific detection of MAPK pathway inhibitors over compounds targeting any other pathway or cellular function. The accuracy of our approach was highlighted in a pilot screen of ~6000 compounds where 40 actives were detected, including 18 MEK, 10 RAF, and 3 ERK inhibitors along with a few compounds representing previously under-characterized inhibitors of the MAPK pathway. One such compound, bafetinib, a second generation BCR/ABL inhibitor, reduced phosphorylation of ERK and when combined with trametinib, both in vitro and in vivo, reduced growth of vemurafenib resistant melanoma cells. While piloted in a model of BRAF-driven melanoma, our results set the stage for using this approach to rapidly generate reporters against any transcriptionally active pathway across a wide variety of disease-relevant cell-based models to expedite drug discovery efforts.

    Topics: Animals; Antineoplastic Agents; Cell Line; Cell Line, Tumor; Drug Discovery; Female; HEK293 Cells; Humans; Melanoma; Melanoma, Cutaneous Malignant; Mice; Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones; Skin Neoplasms; Vemurafenib

2018
Trametinib downregulates survivin expression in RB1-positive KRAS-mutant lung adenocarcinoma cells.
    Biochemical and biophysical research communications, 2018, 06-18, Volume: 501, Issue:1

    High expression levels of survivin in KRAS-mutant lung adenocarcinomas are linked with unfavorable patient outcomes, suggesting that survivin is a promising target for tumor treatment. We found that trametinib, a MEK inhibitor, downregulates survivin expression in the RB1-positive KRAS-mutant lung adenocarcinoma cell lines H358 and H441. In these cell lines, trametinib treatment induced p21 expression and dephosphorylated RB1, leading to sustained suppression of survivin. Knockdown of p21 or RB1 restored survivin expression in trametinib-treated cells, at least partially, which supports the contribution of these molecules to trametinib-mediated survivin suppression. In RB1-negative KRAS-mutant lung adenocarcinoma H2009 cells, survivin downregulation by trametinib was only slight and transient, and trametinib-resistant (TR) cells developed within 1 month of treatment. H2009 TR cells depended much more on survivin for survival than its parental cells, as evidenced by apoptosis induction when survivin was depleted. These findings collectively suggest that trametinib is effective for the treatment of RB1-positive KRAS-mutant lung adenocarcinomas through sustained survivin suppression, but not for RB1-negative lung adenocarcinomas. Thus, the RB1 status could be a biomarker for trametinib application in KRAS-mutant lung adenocarcinomas.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; Gene Knockdown Techniques; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Models, Biological; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Retinoblastoma Binding Proteins; Survivin; Ubiquitin-Protein Ligases

2018
Hemophagocytic lymphohistiocytosis associated with dabrafenib and trametinib combination therapy following pembrolizumab administration for advanced melanoma.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2018, 07-01, Volume: 29, Issue:7

    Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Lung Neoplasms; Lymphohistiocytosis, Hemophagocytic; Melanoma; Middle Aged; Oximes; Prognosis; Pyridones; Pyrimidinones

2018
Trametinib in Histiocytic Sarcoma with an Activating MAP2K1 (MEK1) Mutation.
    The New England journal of medicine, 2018, 05-17, Volume: 378, Issue:20

    Topics: Histiocytic Sarcoma; Humans; Male; MAP Kinase Kinase 1; Metabolic Networks and Pathways; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2018
Clinical resistance associated with a novel MAP2K1 mutation in a patient with Langerhans cell histiocytosis.
    Pediatric blood & cancer, 2018, Volume: 65, Issue:9

    Patients with Langerhans cell histiocytosis (LCH) harbor BRAF V600E and activating mutations of MAP2K1/MEK1 in 50% and 25% of cases, respectively. We evaluated a patient with treatment-refractory LCH for mutations in the RAS-RAF-MEK-ERK pathway and identified a novel mutation in the MAP2K1 gene resulting in a p.L98_K104 > Q deletion and predicted to be auto-activating. During treatment with the MEK inhibitor trametinib, the patient's disease showed significant progression. In vitro characterization of the MAP2K1 p.L98_K104 > Q deletion confirmed its effect on cellular activation of the ERK pathway and drug resistance.

    Topics: Adolescent; Adrenal Cortex Hormones; Butadienes; Combined Modality Therapy; Cytarabine; Disease Progression; Drug Resistance; Drug Therapy, Combination; Enzyme Activation; Exons; HEK293 Cells; Hematopoietic Stem Cell Transplantation; Histiocytosis, Langerhans-Cell; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Signaling System; Molecular Targeted Therapy; Mutation; Nitriles; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyrazoles; Pyridones; Pyrimidinones; Recombinant Fusion Proteins; Sequence Deletion; Thiophenes; Vincristine

2018
BRAF and MEK inhibitor therapy eliminates Nestin-expressing melanoma cells in human tumors.
    Pigment cell & melanoma research, 2018, Volume: 31, Issue:6

    Topics: Antibodies, Neoplasm; Cell Line, Tumor; Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Nestin; Oximes; Phenotype; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2018
Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition.
    Nature medicine, 2018, Volume: 24, Issue:7

    The role of KRAS, when activated through canonical mutations, has been well established in cancer

    Topics: Animals; Cell Line, Tumor; Disease Models, Animal; Esophageal Neoplasms; Gene Amplification; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Piperidines; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidines; Pyrimidinones; Stomach Neoplasms

2018
Dabrafenib and trametinib treatment-associated fevers in metastatic melanoma causing extreme elevation in procalcitonin in the absence of infection.
    Anti-cancer drugs, 2018, Volume: 29, Issue:8

    Febrile illnesses are common in the management of metastatic solid organ malignancies. Traditionally they occur in the setting of immunosuppression and neutropenia owing to cytotoxic therapy necessitating consideration of systemic infections. Systemic markers of inflammation, such as C-reactive protein and procalcitonin (PCT), may be used to assist in determining the aetiology of a fever in such patients. Newer anticancer therapies may cause significant noninfectious fevers and may result in a rise in inflammatory markers, despite the absence of an infection. We present a case of a critically unwell febrile patient being treated with dabrafenib and trametinib for advanced melanoma. The patient had an extreme elevation in PCT in the absence of infection. We discuss the presentation of fevers related to dabrafenib and trametinib therapy in the management of advanced melanoma, and the utility of PCT in the management of fevers in advanced solid organ malignancies.

    Topics: Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Fever; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Sepsis; Skin Neoplasms

2018
Does adjuvant therapy for high-risk melanoma with either immunotherapy or targeted therapy affect therapeutic choices at relapse?
    Clinical advances in hematology & oncology : H&O, 2018, Volume: 16, Issue:5

    Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Chemotherapy, Adjuvant; Combined Modality Therapy; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Immunotherapy; Interferon alpha-2; Interferon-alpha; Ipilimumab; MAP Kinase Kinase 1; Melanoma; Nivolumab; Oximes; Prognosis; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Recombinant Proteins; Recurrence; Skin Neoplasms; Survival Analysis

2018
MEK inhibitor trametinib in combination with gemcitabine regresses a patient-derived orthotopic xenograft (PDOX) pancreatic cancer nude mouse model.
    Tissue & cell, 2018, Volume: 52

    Pancreatic cancer is resistant to treatment and needs precision individualized therapy to improve the outcome of this disease. Previously, we demonstrated that trametinib (TRA), a MEK inhibitor, could inhibit a pancreatic cancer patient-derived orthotopic xenograft (PDOX). In the present study, we show that gemcitabine (GEM) in combination with TRA was more effective than TRA alone. We implanted a patient pancreatic cancer orthotopically in the pancreatic tail of nude mice to establish the PDOX model. After seven weeks of tumor growth, we divided 32 pancreatic-cancer PDOX nude mice into 4 groups of eight: untreated control; GEM (once a week for 2 weeks); TRA (14 consecutive days); GEM + TRA (GEM: once a week for 2 weeks, TRA:14 consecutive days). We found that treated mice on day 14 had significantly reduced tumor volume in comparison to untreated control. TRA and the combination of GEM + TRA therapy significantly inhibited tumor development in comparison to GEM alone. However, GEM + TRA inhibited the PDOX tumor growth significantly greater than TRA alone. These results suggest the clinical potential of the combination of TRA and GEM for pancreatic cancer.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Models, Animal; Gemcitabine; Humans; Mice; Mice, Nude; Pancreatic Neoplasms; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2018
Dasatinib sensitises KRAS-mutant cancer cells to mitogen-activated protein kinase kinase inhibitor via inhibition of TAZ activity.
    European journal of cancer (Oxford, England : 1990), 2018, Volume: 99

    Oncogenic KRAS mutations occur frequently in solid tumours, but no clinically applicable targeted strategy is yet available for treating human cancers with mutant KRAS. Here we aimed to identify a strategy for the treatment of KRAS-driven cancers.. Cell viability and colony forming assays were used to assess the in vitro effect of dasatinib and trametinib as single agents or in combination. Western blot was used to analyse the phosphorylated protein and total protein levels. Xenograft models were used to evaluate the in vivo effect of drug combination on KRAS-driven tumour growth.. Here, we report the discovery of a synergistic interaction between dasatinib (ABL and SRC family kinase inhibitor) and the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib in KRAS-mutant cancer cells. We demonstrated that dasatinib enhanced the antitumour effect of trametinib against the KRAS-mutant cancer models both in vitro and in vivo, and the combination resulted in a significant reduction of cytoplasmic and nucleic TAZ protein level, and therefore decreased downstream protein levels of YAP/TAZ signalling pathway. Furthermore, direct knockdown of TAZ by small interfering RNA was able to increase the sensitivity of KRAS-mutant cells to trametinib treatment.. These results indicate that dasatinib enhances the antitumour activity of MEK inhibitor through inhibition of TAZ activity and identify dasatinib and trametinib combination as a potential strategy for the treatment of KRAS-driven cancers.

    Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Dasatinib; Drug Resistance, Neoplasm; Drug Synergism; Female; Gene Knockdown Techniques; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasms; Phosphoproteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; RNA, Small Interfering; Signal Transduction; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Treatment Outcome; Xenograft Model Antitumor Assays; YAP-Signaling Proteins

2018
Two cases of dabrafenib and trametinib therapy-failed advanced melanoma successfully controlled by nivolumab monotherapy.
    The Journal of dermatology, 2018, Volume: 45, Issue:9

    Although therapies for advanced melanoma have been greatly improved by the development of immune checkpoint inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors, there are still many concerns about the administration of these novel drugs. Therefore, to combine these therapies sequentially at appropriate time points of the disease is important. In this report, we report two cases in which dabrafenib and trametinib therapy for advanced melanoma failed but were successfully controlled by nivolumab monotherapy, and investigated the sera sCD163, CCL22 and CXCL10 as biomarkers for tumor progression. Interestingly, the sera levels of sCD163, CXCL10 and CCL22, both of which are produced by activated tumor-associated macrophages, were increased in parallel with the tumor progression in each case. Because this report presents only two cases, further data will need to be accumulated to provide more fundamental insights into the usefulness of these biomarkers for predicting disease progression in melanoma.

    Topics: Adult; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Disease Progression; Female; Humans; Imidazoles; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Nivolumab; Oximes; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2018
Elimination of melanoma by sortase A-generated TCR-like antibody-drug conjugates (TL-ADCs) targeting intracellular melanoma antigen MART-1.
    Biomaterials, 2018, Volume: 178

    Most tumor-associated proteins are located inside tumor cells and thus are not accessible to current marketed therapeutic monoclonal antibodies or their cytotoxic conjugates. Human leukocyte antigen (HLA) class I can present peptides derived from intracellular tumor-associated proteins and somatically mutated proteins on the cell's surface, forming an HLA/peptide complex as tumor-specific antigens for T cell receptor (TCR) recognition. Therefore, HLA-mediated presentation of intracellular tumor antigen peptides provides a viable way to distinguish tumor cells from normal cells, which is important for broadening antigen selection, especially for antibody-drug conjugates (ADCs) regarding their highly cytotoxic payload. We applied sortase A-mediated conjugation to develop TCR-like ADCs (i.e., EA1 HL-vcMMAE) targeting intracellular MART-1 protein, a melanocyte-differentiating antigen specific for metastatic melanomas, via the cell surface HLA-A2/MART-1

    Topics: Aminoacyltransferases; Animals; Antibody Specificity; Antigen Presentation; Antineoplastic Agents; Bacterial Proteins; Cell Line, Tumor; Cysteine Endopeptidases; Endocytosis; Female; Histocompatibility Antigens Class I; Immunoconjugates; Intracellular Space; MART-1 Antigen; Melanoma; Mice, SCID; Peptides; Protein Binding; Pyridones; Pyrimidinones; Receptors, Antigen, T-Cell

2018
Incidence of Basal Cell Carcinoma and Squamous Cell Carcinoma in Patients on Antiprogrammed Cell Death-1 Therapy for Metastatic Melanoma.
    Journal of immunotherapy (Hagerstown, Md. : 1997), 2018, Volume: 41, Issue:7

    Systemic melanoma therapies have the potential to affect basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cuSCC) development. In this study, we aim to compare the incidence of BCC and cuSCC in patients with metastatic melanoma treated with antiprogrammed cell death-1 (anti-PD1), BRAF inhibitor (BRAFi) monotherapy or dabrafenib and trametinib combination therapy (CombiDT) with a group of control patients having similar risk factors. We reviewed the records of melanoma patients on anti-PD1, BRAFi, or CombiDT, and patients from the High-Risk Melanoma Clinic, Westmead Hospital. We also performed an immunohistochemical analysis of BCCs under anti-PD1 compared with controls using PD1, PD-L1, CD3, CD8, and CD20 stains. For the results, in all, 340 patients were included; 82 on anti-PD1, 134 on BRAFi, 69 on CombiDT, and 55 controls. BRAFi had the highest incidence of BCC (12.7%), followed by CombiDT (10.1%) and anti-PD1 (2.4%). The incidence of BCC was significantly lower in patients on anti-PD1 (2.4% vs. 19.4%; P<0.001) compared with controls. Patients on anti-PD1 were 8.54 times less likely to develop BCC than the controls [hazard ratio, 0.117 (95% confidence interval, 0.026-0.526), P=0.005]. BRAFi and CombiDT showed no significant differences in BCC incidence compared with controls. BRAFi had the highest cuSCC incidence (23.9%), followed by anti-PD1 (7.3%) and CombiDT (2.9%). The incidence of cuSCC was significantly higher in patients on BRAFi (23.9% vs. 3.5%; P<0.001) compared with controls, but anti-PD1 and CombiDT showed no differences in cuSCC incidence compared with controls. Immunohistochemistry analysis of 10 BCC from under anti-PD1 and 8 BCC from controls patients showed that while all BCC had negative PD-L1 staining, the percentage of PD1 staining in anti-PD1 group is significantly lower than that of the control group (independent t test, 8% vs. 26%; P<0.001). In conclusion, our study suggests that anti-PD1 therapy decreases the incidence of BCC, as a result of the PD1/PD-L1 blockade. Future studies investigating the role of anti-PD1 in suppressing or treating BCC may be warranted.

    Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Australia; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Immunotherapy; Incidence; Male; Melanoma; Middle Aged; Neoplasm Staging; Nivolumab; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

2018
In Vitro Screening of Six Protein Kinase Inhibitors for Time-Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug-Drug Interactions.
    Basic & clinical pharmacology & toxicology, 2018, Volume: 123, Issue:6

    Topics: Benzamides; Benzimidazoles; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP2C8 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Indoles; Inhibitory Concentration 50; Microsomes, Liver; Phthalazines; Piperidines; Pyridines; Pyridones; Pyrimidinones; Quinolones; Staurosporine; Thiazoles

2018
MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma.
    Science translational medicine, 2018, 07-04, Volume: 10, Issue:448

    The RAS isoforms are frequently mutated in many types of human cancers, including PAX3/PAX7 fusion-negative rhabdomyosarcoma. Pediatric RMS arises from skeletal muscle progenitor cells that have failed to differentiate normally. The role of mutant RAS in this differentiation blockade is incompletely understood. We demonstrate that oncogenic RAS, acting through the RAF-MEK [mitogen-activated protein kinase (MAPK) kinase]-ERK (extracellular signal-regulated kinase) MAPK effector pathway, inhibits myogenic differentiation in rhabdomyosarcoma by repressing the expression of the prodifferentiation myogenic transcription factor, MYOG. This repression is mediated by ERK2-dependent promoter-proximal stalling of RNA polymerase II at the

    Topics: Animals; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromatin; Enhancer Elements, Genetic; Extracellular Signal-Regulated MAP Kinases; Genes, ras; Humans; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Muscle Development; Myoblasts; Myogenin; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptor, IGF Type 1; Rhabdomyosarcoma; Transcription, Genetic; Xenograft Model Antitumor Assays

2018
Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models.
    Journal of experimental & clinical cancer research : CR, 2018, Jul-09, Volume: 37, Issue:1

    Mounting evidence suggests that RAF-mediated MEK activation plays a crucial role in paradox MAPK (re)activation, leading to resistance and therapeutic failure with agents hitting a single step along the MAPK cascade.. We examined the molecular and functional effects of single and combined BRAF (dabrafenib), pan-RAF (RAF265), MEK (trametinib) and EGFR/HER2 (lapatinib) inhibition, using Western Blot and conservative isobologram analysis to assess functional synergism, and explored genetic determinants of synergistic interactions. Immunoprecipitation based assays were used to detect the interaction between BRAF and CRAF. The Mann-Whitney U test was used for comparing quantitative variables.. Here we demonstrated that a combination of MEK and BRAF inhibitors overcomes paradoxical MAPK activation (induced by BRAF inhibitors) in BRAF-wt/RAS-mut NSCLC and PDAC in vitro. This results in growth inhibitory synergism, both in vitro and in vivo, in the majority (65%) of the cellular models analyzed, encompassing cell lines and patient-derived cancer stem cells and organoids. However, RAS mutational status is not the sole determinant of functional synergism between RAF and MEK inhibitors, as demonstrated in KRAS isogenic tumor cell line models. Moreover, in EGFR-driven contexts, paradoxical MAPK (re)activation in response to selective BRAF inhibition was dependent on EGFR family signaling and could be offset by simultaneous EGFR/HER-2 blockade.. Overall, our data indicate that RAF inhibition-induced paradoxical MAPK activation could be exploited for therapeutic purposes by simultaneously targeting both RAF and MEK (and potentially EGFR family members) in appropriate molecular contexts. KRAS mutation per se does not effectively predict therapeutic synergism and other biomarkers need to be developed to identify patients potentially deriving benefit from combined BRAF/MEK targeting.

    Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Humans; Imidazoles; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplastic Stem Cells; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2018
The clinically approved MEK inhibitor Trametinib efficiently blocks influenza A virus propagation and cytokine expression.
    Antiviral research, 2018, Volume: 157

    Influenza A virus (IAV) infections are still a major global threat for humans, especially for the risk groups of young children and the elderly. Annual epidemics and sporadically occurring pandemics highlight the necessity of effective antivirals that can limit viral replication. The currently licensed antiviral drugs target viral factors and are prone to provoke viral resistance. In infected host cells IAV induces various cellular signaling cascades. The Raf/MEK/ERK signaling cascade is indispensable for IAV replication because it triggers the nuclear export of newly assembled viral ribonucleoproteins (vRNPs). Inhibition of this cascade limits viral replication. Thus, next to their potential in anti-tumor therapy, inhibitors targeting the Raf/MEK/ERK signaling cascade came into focus as potential antiviral drugs. The first licensed MEK inhibitor Trametinib (GSK-1120212) is used for treatment of malignant melanoma, being highly selective and having a promising side effect profile. Since Trametinib may be qualified for a repurposing approach that would significantly shorten development time for an anti-flu use, we evaluated its antiviral potency and mode of action. In this study, we describe that Trametinib efficiently blocks replication of different IAV subtypes in vitro and in vivo. The broad antiviral activity against various IAV strains was due to its ability to interfere with export of progeny vRNPs from the nucleus. The compound also limited hyper-expression of several cytokines. Thus, we show for the first time that a clinically approved MEK inhibitor acts as a potent anti-influenza agent.

    Topics: Animals; Antineoplastic Agents; Antiviral Agents; Cell Line; Cytokines; Drug Repositioning; Humans; Immunologic Factors; Influenza A virus; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Virus Replication

2018
Healthcare resource utilization in patients with metastatic melanoma receiving first-line therapy with dabrafenib + trametinib versus nivolumab or pembrolizumab monotherapy.
    Current medical research and opinion, 2018, Volume: 34, Issue:12

    To compare healthcare resource utilization (HRU) between patients with metastatic melanoma (MM) initiated on first-line (1L) combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib (D + T; oral) and those initiated on 1 L monotherapy with the anti-PD1 monoclonal antibodies nivolumab or pembrolizumab (N/P; intravenous).. Patients with melanoma initiated on D + T or N/P from Q1/2014 to Q2/2016 (defined as 1 L treatment for MM) were identified in the Truven MarketScan database. Entropy balancing was used to reweight the N/P cohort in order to make it comparable to the D + T cohort with respect to the mean and variance of baseline covariates. HRU outcomes during 1 L therapy, reported per patient-year (PPY), were described and compared between the two cohorts post-weighting (i.e. independently of baseline covariates).. Of the 445 patients included, 202 and 243 were initiated on D + T and N/P, respectively. After weighting, patients initiated on N/P had more outpatient visits for drug administration during 1 L therapy than those initiated on D + T (difference = 18.6 visits PPY [95% CI = 16.0-21.1]). Patients initiated on N/P also had more outpatient office visits for reasons other than drug administration (difference = 8.1 visits PPY [95% CI = 1.9-13.7]). No significant differences were observed for other HRU parameters (i.e. inpatient admissions, inpatient days, and emergency department visits during 1 L therapy).. HRU during 1 L therapy was generally similar between patients initiated on D + T and N/P. Nonetheless, patients initiated on N/P had more outpatient visits, including more outpatient visits for reasons unrelated to drug administration.

    Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Nivolumab; Oximes; Patient Acceptance of Health Care; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies

2018
Metabolic Response to BRAF-MEK Combination Therapy in Cecal Neuroendocrine Carcinoma With BRAFV600E Mutation and Refractory Lactic Acidosis.
    Clinical nuclear medicine, 2018, Volume: 43, Issue:9

    We report the results of serial F-FDG PET/CT investigations in a 49-year-old woman presenting with an advanced cecal high-grade neuroendocrine carcinoma harboring a somatic BRAF mutation. Patient was refractory to standard chemotherapy regimen showing life-threatening hyperlactatemia. Early after the beginning of BRAF-MEK therapy (dabrafenib and trametinib), impressive improvement in PET/CT imaging was achieved. The pathological F-FDG uptake in cecal primary tumor as well as in nodal, hepatic, and bone metastases drastically decreased. Moreover, the reduction of total lesion glycolysis on PET/CT images was strictly related to extraordinary patient clinical response and lactic acid level normalization.

    Topics: Acidosis, Lactic; Carcinoma, Neuroendocrine; Combined Modality Therapy; Female; Humans; Imidazoles; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Mutation; Oximes; Positron Emission Tomography Computed Tomography; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

2018
Pooled genome-wide CRISPR screening for basal and context-specific fitness gene essentiality in
    eLife, 2018, 07-27, Volume: 7

    Topics: Animals; Computational Biology; CRISPR-Cas Systems; Drosophila; Drug Interactions; Gene Expression Regulation; Gene Knockout Techniques; Gene Library; Genes, Essential; Genetic Fitness; Genome-Wide Association Study; Pharmacogenetics; Phenotype; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Sirolimus

2018
Mutant LKB1 Confers Enhanced Radiosensitization in Combination with Trametinib in KRAS-Mutant Non-Small Cell Lung Cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2018, 11-15, Volume: 24, Issue:22

    Topics: AMP-Activated Protein Kinase Kinases; Animals; Antineoplastic Agents; Autophagy; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Lung Neoplasms; Mice; Mutation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Radiation Tolerance; Reactive Oxygen Species; Signal Transduction; Xenograft Model Antitumor Assays

2018
Dabrafenib-trametinib combination in 'field-practice': an Italian experience.
    Future oncology (London, England), 2018, Volume: 14, Issue:20

    This observational study investigates the effectiveness and safety of dabrafenib/trametinib combination in patients with metastatic melanoma.. Seventy-six patients treated with dabrafenib/trametinib (150 mg twice daily/2 mg once daily) were included.. Median progression-free survival was 9 months (95% CI: 7-11) and median overall survival was 14 months (11-16); disease control rate was 72%. Nine patients (12%) experienced a complete response. Of these, seven presented one metastatic site, none had lung or CNS metastasis, and none had elevated baseline lactate dehydrogenase (LDH) levels. Overall, subgroup analysis for patients with adverse prognostic features led to similar results. No new safety signals were reported.. Dabrafenib/trametinib combination can be effective and well-tolerated also in a heterogeneous 'real life' population comprising patients with adverse prognostic features.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Follow-Up Studies; Humans; Imidazoles; Italy; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Neoplasms; Oximes; Prognosis; Pyridones; Pyrimidinones; Treatment Outcome; Young Adult

2018
Possible immune adverse events as predictors of durable response to BRAF inhibitors in patients with BRAF V600-mutant metastatic melanoma.
    European journal of cancer (Oxford, England : 1990), 2018, Volume: 101

    BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are among the cornerstones of metastatic melanoma therapy demonstrating excellent response rates with duration of 7-12 m. Long-term benefit from these agents was reported in patients with normal lactate dehydrogenase (LDH) and less than three disease sites. However, a treatment-dependent marker for long-term efficacy is lacking. Data suggest that immune-related adverse events (irAEs) are associated with clinical benefit in patients treated with immunotherapy and that response to BRAF/MEK therapy may have an underlying immune mechanism. We hypothesised that AEs with an underlying immune mechanism may be associated with a durable response to targeted therapy. We retrospectively identified a cohort of 78 BRAF V600-mutant metastatic melanoma patients treated with BRAFi or BRAFi + MEKi between November 2010 and November 2013. Four treatment-related AEs including vitiligo, uveitis, erythema nodosum and keratitis sicca were defined as irAEs of interest. Retrospective analysis of AEs in relationship to progression-free survival (PFS), disease burden and LDH levels was performed. Median PFS (mPFS) for all patients was 7.5 months with responses ongoing in eight patients as of April 2017. Ten patients were identified with the AEs defined previously. Cox regression analysis revealed a very strong association between those AEs and PFS; mPFS was 42.8 m in patients with at least one AE versus 6.1 m in those without an AE (hazard ratio [HR] 0.22, p = 0.002). This association was independent of LDH levels and disease burden (HR 0.24, p = 0.035). This analysis demonstrates a strong association between immune AEs and durable response to targeted therapy and may provide a treatment-related biomarker to estimate the outcome of therapy.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arthralgia; Azetidines; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Diseases; Skin Neoplasms; Vemurafenib; Young Adult

2018
Trametinib for progressive pediatric low-grade gliomas.
    Journal of neuro-oncology, 2018, Volume: 140, Issue:2

    Pediatric pilocytic astrocytomas (PAs) are low grade gliomas and the most common brain tumors in children. They often represent a therapeutic challenge when incompletely resected as they can recur and progress despite the use of several lines of chemotherapeutic agents or even radiation therapy. Genetic alterations leading to activation of the mitogen-activated-protein-kinase pathway are a hallmark of this disease and offer an interesting therapeutic alternative through the use of targeted inhibitors.. Here, we describe six children with sporadic PA who were treated with trametinib, a MEK inhibitor, following progression under conventional therapies. Retrospective chart review was performed.. The median age at diagnosis was 2.3 years (y) old [range 11 months (m)-8.5 y old]. KIAA1549-BRAF fusion was identified in five cases, and hotspot FGFR1/NF1/PTPN11 mutations in one. All patients received at least one previous line of chemotherapy (range 1-4). The median time on treatment was 11 m (range 4-20). Overall, we observed two partial responses and three minor responses as best response; three of these patients are still on therapy. Treatment was discontinued in the patient with progressive disease. The most frequent toxicities were minor to moderately severe skin rash and gastro-intestinal symptoms. Two patients had dose reduction due to skin toxicity. Quality of life was excellent with decreased hospital visits and a close to normal life.. Trametinib appears to be a suitable option for refractory pediatric low-grade glioma and warrants further investigations in case of progression.

    Topics: Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Child; Child, Preschool; Disease Progression; Female; Humans; Infant; Male; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Retreatment; Retrospective Studies

2018
Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer.
    Cancer science, 2018, Volume: 109, Issue:10

    Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non-small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide-3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR-TKI-resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single-agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal-epithelial transition factor amplification, induction of epithelial-to-mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long-term treatment with the combination therapy induced the conversion from EMT to mesenchymal-to-epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR-TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR-TKIs.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; Epithelial-Mesenchymal Transition; ErbB Receptors; Female; Humans; Imidazoles; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Mutation; Oxazepines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; Xenograft Model Antitumor Assays

2018
Targeting MEK in a Translational Model of Histiocytic Sarcoma.
    Molecular cancer therapeutics, 2018, Volume: 17, Issue:11

    Histiocytic sarcoma in humans is an aggressive orphan disease with a poor prognosis as treatment options are limited. Dogs are the only species that spontaneously develops histiocytic sarcoma with an appreciable frequency, and may have value as a translational model system. In the current study, high-throughput drug screening utilizing histiocytic sarcoma cells isolated from canine neoplasms identified these cells as particularly sensitive to a MEK inhibitor, trametinib. One of the canine cell lines carries a mutation in PTPN11 (E76K), and another one in KRAS (Q61H), which are associated with the activation of oncogenic MAPK signaling. Both mutations were previously reported in human histiocytic sarcoma. Trametinib inhibited sensitive cell lines by promoting cell apoptosis, indicated by a significant increase in caspase 3/7. Furthermore,

    Topics: Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dogs; Down-Regulation; Female; Histiocytic Sarcoma; Liver; MAP Kinase Signaling System; Mice, Inbred NOD; Mice, SCID; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Molecular Targeted Therapy; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Survival Analysis; Translational Research, Biomedical; Up-Regulation; Xenograft Model Antitumor Assays

2018
Tattoo-associated complications of metastatic melanoma treated with dabrafenib and trametinib.
    Melanoma research, 2018, Volume: 28, Issue:5

    Topics: Adult; Female; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Tattooing

2018
ERRα suppression enhances the cytotoxicity of the MEK inhibitor trametinib against colon cancer cells.
    Journal of experimental & clinical cancer research : CR, 2018, Sep-05, Volume: 37, Issue:1

    ERRα, a constitutive transcription factor that regulates energy metabolism, plays an important role in the progression of various tumours. However, its role in cell survival and proliferation and its implication in targeted therapy in colon cancer remains elusive.. The expression of ERRα in colon cancer tissues and cell lines was detected by using western blotting and immunohistochemistry. A wound healing assay and a transwell assay were performed to examine the migration and invasion of the colon cancer cells. A cell viability assay, clonogenic assay, western blot assay and the dual-luciferase reporter assay were employed to study the interaction between trametinib (inhibitor of MEK) and EGF treatment. Flow cytometry, western blotting, quantitative reverse-transcription polymerase chain reaction and xenograft studies were used to identify whether the combination of trametinib and simvastatin had a synergistic effect.. ERRα positively regulated the cell proliferation, migration and invasion of colon cancer cells, and the suppression of ERRα completely reduced the EGF treatment-induced proliferation of colon cancer cells. Further investigation showed that trametinib partially restrained the up-regulation of ERRα induced by the EGF treatment, and ERRα inhibition increased the sensitivity of colon cancer cells to trametinib. At last, we combined trametinib with simvastatin, a common clinically used drug with a new reported function of transcriptional activity inhibition of ERRα, and found that this combination produced a synergistic effect in inhibiting the proliferation and survival of colon cancer cells in vitro as well as in vivo.. The present data indicated that ERRα acted as an oncogene in colon cancer cells, and the combined targeting of ERRα and MEK might be a promising therapeutic strategy for colon cancer treatment.

    Topics: Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Colonic Neoplasms; Epidermal Growth Factor; ERRalpha Estrogen-Related Receptor; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Mice; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptors, Estrogen; Signal Transduction; Xenograft Model Antitumor Assays

2018
Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand.
    Cell death & disease, 2018, 09-24, Volume: 9, Issue:10

    Inhibition of epidermal growth factor receptor (EGFR) signaling by small molecule kinase inhibitors and monoclonal antibodies has proven effective in the treatment of multiple cancers. In contrast, metastatic breast cancers (BC) derived from EGFR-expressing mammary tumors are inherently resistant to EGFR-targeted therapies. Mechanisms that contribute to this inherent resistance remain poorly defined. Here, we show that in contrast to primary tumors, ligand-mediated activation of EGFR in metastatic BC is dominated by STAT1 signaling. This change in downstream signaling leads to apoptosis and growth inhibition in response to epidermal growth factor (EGF) in metastatic BC cells. Mechanistically, these changes in downstream signaling result from an increase in the internalized pool of EGFR in metastatic cells, increasing physical access to the nuclear pool of STAT1. Along these lines, an EGFR mutant that is defective in endocytosis is unable to elicit STAT1 phosphorylation and apoptosis. Additionally, inhibition of endosomal signaling using an EGFR inhibitor linked to a nuclear localization signal specifically prevents EGF-induced STAT1 phosphorylation and cell death, without affecting EGFR:ERK1/2 signaling. Pharmacologic blockade of ERK1/2 signaling through the use of the allosteric MEK1/2 inhibitor, trametinib, dramatically biases downstream EGFR signaling toward a STAT1-dominated event, resulting in enhanced EGF-induced apoptosis in metastatic BC cells. Importantly, combined administration of trametinib and EGF also facilitated an apoptotic switch in EGFR-transformed primary tumor cells, but not normal mammary epithelial cells. These studies reveal a fundamental distinction for EGFR function in metastatic BC. Furthermore, the data demonstrate that pharmacological biasing of EGFR signaling toward STAT1 activation is capable of revealing the apoptotic function of this critical pathway.

    Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Endocytosis; Epidermal Growth Factor; ErbB Receptors; Gefitinib; Humans; Ligands; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Mice; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; STAT1 Transcription Factor

2018
New features in MEK retinopathy.
    BMC ophthalmology, 2018, Sep-14, Volume: 18, Issue:Suppl 1

    The use of molecularly targeted therapy is becoming widespread in oncology. These agents cause tumour-specific genetic alterations in signal transduction pathways, hence less generalised toxicity. Dabrafenib, a BRAF inhibitor and Trametinib, a MEK inhibitor are two molecularly targeted agents recently approved for treatment of advanced, unresectable melanomas. MEK retinopathy is a recently introduced term describing retinal toxicity secondary to MEK inhibitors.. A 71-year-old man presented with 'circular, green patches' in his central vision for 2 weeks. He had multiple relapsed stage IV BRAF gene mutant malignant melanoma. He was on treatment with Dabrafenib (Tafinlar) for 7 months and Trametinib (Mekinist) for 4 months respectively. The fundus looked normal. The OCT scan showed bilateral symmetrical cystoid macular edema, intraretinal and subretinal fluid, thickening of elliposoid zone and subretinal granular deposits. The symptoms resolved with temporary cessation of chemotherapy but OCT signs persisted.. This case report identifies two new remarkable features of MEK retinopathy as thickening of ellipsoid zone and 'starry sky' pattern of distribution of subretinal granular deposits. These changes signify photoreceptors/ RPE toxicity and dysfunction. The subretinal granular deposits showed increased autofluorescence suggested abnormal lipofuscin clearance due to RPE dysfunction. The molecularly targeted therapy has revolutionized the cancer treatment and increased the survival rate. These agents are relatively new and recently approved for clinical use and most of them are associated with ocular toxicities. Awareness of ocular symptoms, side-effect profile of drugs, monitoring regime and liaison between oncologist and eye care professional with ocular imaging is key to early diagnosis and management of ocular adverse events.

    Topics: Aged; Humans; Imidazoles; Macular Edema; Male; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Oximes; Paraneoplastic Syndromes, Ocular; Photoreceptor Cells, Vertebrate; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Diseases; Retinal Pigment Epithelium; Skin Neoplasms; Subretinal Fluid; Tomography, Optical Coherence

2018
In vivo effects of short- and long-term MAPK pathway inhibition against neuroblastoma.
    Journal of pediatric surgery, 2018, Volume: 53, Issue:12

    It was reported that almost 80% of relapsed neuroblastomas showed MAPK pathway mutations. In our previous study, both trametinib (MEK inhibitor) and CH5126766 (RAF/MEK inhibitor) showed in vitro antitumor effects on neuroblastoma cells with ERK phosphorylation (pERK). In this study, we analyzed the in vivo effects of MAPK pathway inhibition in neuroblastoma xenografts.. Xenograft mice with IMR5, CHP-212, or SK-N-AS received daily oral administration of either trametinib or CH5126766 for two weeks (short term) or eight weeks (long term). The tumors were measured twice weekly and harvested after treatment for histopathological analyses, including pERK and Ki67 immunohistochemistry.. In short-term treatment, both inhibitors showed significant growth inhibition in CHP-212 and SK-N-AS xenografts, which were pERK-positive before treatment. The number of pERK- and Ki67-positive cells decreased after treatment. Conversely, IMR5 xenografts, which were pERK-negative, were resistant to treatment. During long-term treatment, SK-N-AS xenografts started to regrow from about six weeks with partial differentiation. pERK-positive cells reincreased in these regrown tumors.. MAPK pathway inhibition was effective for treating pERK-positive neuroblastoma in vivo. Therefore, pERK immunohistochemistry might be a convenient biomarker for MAPK pathway inhibition in neuroblastoma treatment. However, neuroblastomas developed acquired drug resistance after long-term treatment. Further studies to overcome acquired resistance are needed.

    Topics: Animals; Cell Line, Tumor; Coumarins; eIF-2 Kinase; Female; Humans; Immunohistochemistry; Ki-67 Antigen; Mice; Mitogen-Activated Protein Kinases; Neoplasm Recurrence, Local; Neuroblastoma; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2018
Cardiac tamponade induced by dabrafenib and trametinib combination therapy for melanoma: Case report.
    Medicine, 2018, Volume: 97, Issue:44

    BRAF and MEK inhibitors (BRAF/MEKi) are targeted therapy for proto-oncogene BRAF mutated metastatic unresectable melanoma. Compared to monotherapy, an increased cardiovascular toxicity is reported with the combination of Dabrafenib and Trametinib. This case report documents Grade 4 cardiac treatment emergent adverse effect of pericardial effusion and cardiac tamponade induced by this combination therapy.. A 52 year old man presented with clinical stage II unresectable melanoma with BRAF mutation, was initiated on treatement with Dabrafenib and Trametinib. He complained of generalised edema and increased his weight by 27 kg. This progressed to shortness of breath and he underwent echocardiogram which revealed cardiac tamponade.. Emergent pericardiocentesis was performed. No definited pathology was demonstrated in laboratory analysis of pericardial fluid. Re- initiating treatment resulted in cardiac tamponade and pericardiotomy was performed by video-assisted thoracic surgical (VATS). Pericardial biopsy revealed nonspecific chronic inflammation.. Discontinuation of treatment with Dabrafenib and Trametinib and diuretics resolved peripheral edema. Cardiac function normalized after pericardiocentesis and pericardiotomy.. Treatment with Dabrafenib and Trametinib caused significant peripheral edema and pericardial effusion resulting in cardiac tamponade. Naranjo score suggests probable association of treatment induced pericardial effusion and cardiac tamponade.. This is the first documented report of pericardial effusion and cardiac tamponade induced by Dabrafenib and Trametinib. Cardiac toxicity of BRAF/MEK inhibitors is rare but clinicans must monitor for treatment emergent adverse effects.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Cardiac Tamponade; Humans; Imidazoles; Male; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Oximes; Pericardiectomy; Proto-Oncogene Mas; Pyridones; Pyrimidinones; Skin Neoplasms; Thoracic Surgery, Video-Assisted

2018
Microneedle-Assisted Topical Delivery of Photodynamically Active Mesoporous Formulation for Combination Therapy of Deep-Seated Melanoma.
    ACS nano, 2018, 12-26, Volume: 12, Issue:12

    Topical treatment using photodynamic therapy (PDT) for many types of skin cancers has largely been limited by the inability of existing photosensitizers to penetrate into the deep skin tissue. To overcome these problems, we developed a mesoporous nanovehicle with dual loading of photosensitizers and clinically relevant drugs for combination therapy, while utilizing microneedle technology to facilitate their penetration into deep skin tissue. Sub-50 nm photodynamically active mesoporous organosilica nanoparticles were synthesized with photosensitizers covalently bonded to the silica matrix, which dramatically increased the quantum yield and photostability of these photosensitizers. The mesopores of the nanoparticles were further loaded with small-molecule inhibitors, i. e., dabrafenib and trametinib, that target the hyperactive mitogen-activated protein kinase (MAPK) pathway for melanoma treatment. As-prepared empty nanovehicle was cytocompatible with normal skin cells in the dark, while NIR-irradiated drug-loaded nanovehicle showed a synergistic killing effect on skin cancer cells mainly through reactive oxygen species and caspase-activated apoptosis. The nanovehicle could significantly inhibit the proliferation of tumor cells in a 3D spheroid model in vitro. Porcine skin fluorescence imaging demonstrated that microneedles could facilitate the penetration of nanovehicle across the epidermis layer of skin to reach deep-seated melanoma sites. Tumor regression studies in a xenografted melanoma mouse model confirmed superior therapeutic efficacy of the nanovehicle through combinational PDT and targeted therapy.

    Topics: Administration, Topical; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Combined Modality Therapy; Drug Delivery Systems; Female; Heterografts; Humans; Imidazoles; Indoles; Isoindoles; Melanoma; Mice, Nude; Nanostructures; Needles; Oxidative Stress; Oximes; Photochemotherapy; Photosensitizing Agents; Pyridones; Pyrimidinones; Silicon Dioxide; Skin Neoplasms

2018
A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers.
    Genome medicine, 2018, 11-27, Volume: 10, Issue:1

    Mutations in KRAS are frequent in human cancer, yet effective targeted therapeutics for these cancers are still lacking. Attempts to drug the MEK kinases downstream of KRAS have had limited success in clinical trials. Understanding the specific genomic vulnerabilities of KRAS-driven cancers may uncover novel patient-tailored treatment options.. We first searched for synthetic lethal (SL) genetic interactions with mutant RAS in yeast with the ultimate aim to identify novel cancer-specific targets for therapy. Our method used selective ploidy ablation, which enables replication of cancer-specific gene expression changes in the yeast gene disruption library. Second, we used a genome-wide CRISPR/Cas9-based genetic screen in KRAS mutant human colon cancer cells to understand the mechanistic connection between the synthetic lethal interaction discovered in yeast and downstream RAS signaling in human cells.. We identify loss of the endoplasmic reticulum (ER) stress sensor IRE1 as synthetic lethal with activated RAS mutants in yeast. In KRAS mutant colorectal cancer cell lines, genetic ablation of the human ortholog of IRE1, ERN1, does not affect growth but sensitizes to MEK inhibition. However, an ERN1 kinase inhibitor failed to show synergy with MEK inhibition, suggesting that a non-kinase function of ERN1 confers MEK inhibitor resistance. To investigate how ERN1 modulates MEK inhibitor responses, we performed genetic screens in ERN1 knockout KRAS mutant colon cancer cells to identify genes whose inactivation confers resistance to MEK inhibition. This genetic screen identified multiple negative regulators of JUN N-terminal kinase (JNK) /JUN signaling. Consistently, compounds targeting JNK/MAPK8 or TAK1/MAP3K7, which relay signals from ERN1 to JUN, display synergy with MEK inhibition.. We identify the ERN1-JNK-JUN pathway as a novel regulator of MEK inhibitor response in KRAS mutant colon cancer. The notion that multiple signaling pathways can activate JUN may explain why KRAS mutant tumor cells are traditionally seen as highly refractory to MEK inhibitor therapy. Our findings emphasize the need for the development of new therapeutics targeting JUN activating kinases, TAK1 and JNK, to sensitize KRAS mutant cancer cells to MEK inhibitors.

    Topics: Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; Colonic Neoplasms; Endoplasmic Reticulum Stress; Endoribonucleases; HEK293 Cells; Humans; MAP Kinase Kinase Kinases; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-jun; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Unfolded Protein Response; Yeasts

2018
Xanthogranulomatous reaction to trametinib for metastatic malignant melanoma.
    Cutis, 2018, Volume: 102, Issue:4

    Trametinib, a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, has demonstrated great promise in treating metastatic melanoma associated with BRAF V600E and V600K mutations; however, it also is highly associated with cutaneous adverse events (AEs). As both BRAF and MEK inhibitors become increasingly used to treat malignant melanoma, it is important to better characterize these AEs so that we can manage them. Herein, we present a case of a 66-year-old man who developed erythematous scaly papules on the face and bilateral upper extremities after beginning therapy with trametinib. The severity of the reaction worsened on trametinib monotherapy compared to combination therapy with a BRAF inhibitor. Biopsy revealed a xanthogranulomatous reaction.

    Topics: Acrylonitrile; Aged; Aniline Compounds; Antineoplastic Agents; Diagnosis, Differential; Granuloma; Humans; Male; Melanoma; Neoplasm Staging; Pyridones; Pyrimidinones; Skin Neoplasms; Xanthomatosis

2018
MEK inhibition enhances oncolytic virus immunotherapy through increased tumor cell killing and T cell activation.
    Science translational medicine, 2018, 12-12, Volume: 10, Issue:471

    Melanoma is an aggressive cutaneous malignancy, but advances over the past decade have resulted in multiple new therapeutic options, including molecularly targeted therapy, immunotherapy, and oncolytic virus therapy. Talimogene laherparepvec (T-VEC) is a herpes simplex type 1 oncolytic virus, and trametinib is a MEK inhibitor approved for treatment of melanoma. Therapeutic responses with T-VEC are often limited, and BRAF/MEK inhibition is complicated by drug resistance. We observed that the combination of T-VEC and trametinib resulted in enhanced melanoma cell death in vitro. Further, combination treatment resulted in delayed tumor growth and improved survival in mouse models. Tumor regression was dependent on activated CD8

    Topics: Animals; B7-H1 Antigen; Basic-Leucine Zipper Transcription Factors; Biological Products; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Cytotoxicity, Immunologic; Dendritic Cells; Disease Models, Animal; Herpesvirus 1, Human; Humans; Immunocompetence; Immunotherapy; Lymphocyte Activation; Melanoma; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Oncolytic Virotherapy; Oncolytic Viruses; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Repressor Proteins; Survival Analysis; T-Lymphocytes; Treatment Outcome; Tumor Microenvironment; Virus Replication; Xenograft Model Antitumor Assays

2018
Knockdown of arsenic resistance protein 2 inhibits human glioblastoma cell proliferation through the MAPK/ERK pathway.
    Oncology reports, 2018, Volume: 40, Issue:6

    It is generally known that glioblastoma is the most common primary malignant brain tumor and that it is highly aggressive and deadly. Although surgical and pharmacological therapies have made long‑term progress, glioblastoma remains extremely lethal and has an uncommonly low survival rate. Therefore, further elucidation of the molecular mechanisms of glioblastoma initiation and its pathological processes are urgent. Arsenic resistance protein 2 (Ars2) is a highly conserved gene, and it has been found to play an important role in microRNA biosynthesis and cell proliferation in recent years. Furthermore, absence of Ars2 results in developmental death in Drosophila, zebrafish and mice. However, there are few studies on the role of Ars2 in regulating tumor development, and the mechanism of its action is mostly unknown. In the present study, we revealed that Ars2 is involved in glioblastoma proliferation and we identified a potential mechanistic role for it in cell cycle control. Our data demonstrated that Ars2 knockdown significantly repressed the proliferation and tumorigenesis abilities of glioblastoma cells in vitro and in vivo. Further investigation clarified that Ars2 deficiency inhibited the activation of the MAPK/ERK pathway, leading to cell cycle arrest in the G1 phase, resulting in suppression of cell proliferation. These findings support the conclusion that Ars2 is a key regulator of glioblastoma progression.

    Topics: Animals; Brain Neoplasms; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Disease Progression; Female; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Glioblastoma; Humans; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Mice, SCID; Nuclear Proteins; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2018
NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination.
    Science (New York, N.Y.), 2018, 12-21, Volume: 362, Issue:6421

    Molecularly targeted therapies aim to obstruct cell autonomous programs required for tumor growth. We show that mitogen-activated protein kinase (MAPK) and cyclin-dependent kinase 4/6 inhibitors act in combination to suppress the proliferation of KRAS-mutant lung cancer cells while simultaneously provoking a natural killer (NK) cell surveillance program leading to tumor cell death. The drug combination, but neither agent alone, promotes retinoblastoma (RB) protein-mediated cellular senescence and activation of the immunomodulatory senescence-associated secretory phenotype (SASP). SASP components tumor necrosis factor-α and intercellular adhesion molecule-1 are required for NK cell surveillance of drug-treated tumor cells, which contributes to tumor regressions and prolonged survival in a KRAS-mutant lung cancer mouse model. Therefore, molecularly targeted agents capable of inducing senescence can produce tumor control through non-cell autonomous mechanisms involving NK cell surveillance.

    Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Cellular Senescence; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cytostatic Agents; Cytotoxicity, Immunologic; Humans; Immunologic Surveillance; Intercellular Adhesion Molecule-1; Killer Cells, Natural; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Purines; Pyridines; Pyridones; Pyrimidinones; Retinoblastoma Protein; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

2018
Uveitis and Papillitis in the Setting of Dabrafenib and Trametinib Therapy for Metastatic Melanoma: A Case Report.
    Ocular immunology and inflammation, 2018, Volume: 26, Issue:4

    To report the diagnosis of acute VKH-like syndrome as a complication from dabrafenib (a serine/threonine inhibitor of BRAF V600) and trametinib (a MEK inhibitor). In combination, these targeted agents have been shown to prolong overall survival and progression free survival in BRAF mutant metastatic melanoma.. Retrospective medical chart review including radiologic and ophthalmologic investigations.. A patient with metastatic melanoma being treated with dabrafenib and trametinib for 2 months presented with 1 week of visual blurring. He had developed bilateral optic disc swelling and uveitis that responded to pulsed steroid therapy.. VKH-like syndrome is a rare but serious complication of targeted therapy that should be considered when evaluating a patient with visual disturbances on dabrafenib and trametinib therapy.

    Topics: Antineoplastic Agents; Disease-Free Survival; Drug Therapy, Combination; Humans; Imidazoles; Male; Melanoma; Middle Aged; Optic Disk; Oximes; Papilledema; Pyridones; Pyrimidinones; Skin Neoplasms; Tomography, Optical Coherence; Uveitis

2018
Bilateral Ischemic Retinal Vasculitis in Metastatic Cutaneous Melanoma Patient Treated with Dabrafenib and Trametinib: A Case Report.
    Ocular immunology and inflammation, 2018, Volume: 26, Issue:5

    Topics: Antineoplastic Agents; Drug Therapy, Combination; Female; Fluorescein Angiography; Fundus Oculi; Humans; Imidazoles; Ischemia; MAP Kinase Kinase 1; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Vasculitis; Retinal Vessels; Skin Neoplasms

2018
Pleural Metastasis From Cutaneous Malignant Melanoma.
    Journal of bronchology & interventional pulmonology, 2018, Volume: 25, Issue:1

    Topics: Aged; Antineoplastic Agents; Biopsy; Diagnosis, Differential; Humans; Male; Melanoma; Melanoma, Cutaneous Malignant; Neoplasms, Second Primary; Pleura; Pleural Cavity; Pleural Neoplasms; Positron-Emission Tomography; Pyridones; Pyrimidinones; Skin Neoplasms

2018
Brugada syndrome induced by BRAF and MEK inhibitors in a melanoma patient.
    European heart journal, 2017, 07-14, Volume: 38, Issue:27

    Topics: Antineoplastic Combined Chemotherapy Protocols; Brugada Syndrome; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2017
Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells.
    Scientific reports, 2017, 03-28, Volume: 7

    Synovial sarcoma (SS) is a rare high-grade malignant mesenchymal tumour with a relatively poor prognosis despite intensive multimodal therapy. Although pazopanib, a multi-kinase inhibitor, is often used for advanced SS, most cases eventually become resistant to pazopanib. In the present study, we investigated the mechanisms of acquired pazopanib resistance in SS. To examine acquired pazopanib resistance, two SS cell lines, SYO-1 and HS-SY-II, were isolated after multiple selection steps with increasing concentrations of pazopanib. SYO-1 was also used in vivo. Then, pazopanib-resistant clones were investigated to assess potential mechanisms of acquired pazopanib resistance. Stable pazopanib-resistant clones were established and exhibited enhanced cell cycle progression, cell growth with increased ERK1/2 phosphorylation, and higher sensitivity than parental cells to a MEK-inhibitor, trametinib, both in vitro and in vivo. Furthermore, addition of low-dose trametinib partially reversed the pazopanib resistance. In the pazopanib-resistant clones, dual specificity phosphatase 6 (DUSP6) was downregulated. Inhibition of DUSP6 expression in parental HS-SY-II cells partially recapitulated acquired pazopanib resistance. Acquired pazopanib resistance in SS was associated with activation of ERK1/2 through downregulation of DUSP6 expression. Simultaneous treatment with pazopanib and a MEK inhibitor could be a promising strategy to overcome pazopanib resistance in SS.

    Topics: Animals; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Dual Specificity Phosphatase 6; Female; Humans; Indazoles; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-raf; Pyridones; Pyrimidines; Pyrimidinones; ras Proteins; Sarcoma, Synovial; Sulfonamides

2017
Systemic therapy for previously untreated advanced BRAF-mutated melanoma: navigating a shifting landscape.
    Immunotherapy, 2017, Volume: 9, Issue:5

    Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Clinical Trials as Topic; Costimulatory and Inhibitory T-Cell Receptors; Humans; Immunotherapy; MAP Kinase Kinase Kinases; Melanoma; Molecular Targeted Therapy; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2017
An UPLC-MS/MS method for the quantification of BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (cobimetinib, trametinib, binimetinib) in human plasma. Application to treated melanoma patients.
    Clinica chimica acta; international journal of clinical chemistry, 2017, Volume: 470

    Targeted therapies for cancers are fast-growing therapies. For instance kinase inhibitors such as BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are increasingly used to treat malignant melanoma. The metabolic profile of these drugs can result in great interindividual variability, justifying therapeutic drug monitoring (TDM). We describe a rapid and specific method for quantification of 2 BRAFi (vemurafenib, dabrafenib) and 3 MEKi (cobimetinib, trametinib and binimetinib). Chromatography was performed on a Waters Acquity-UPLC system with CORTECS C18+ column, under a gradient of 10% acetic acid in water/acetonitrile. An Acquity-TQD® with electrospray ionization was used for detection. Samples were prepared by solid phase extraction (Oasis® MCX microElution) before injection in the system. Calibration curves ranges from 0.4 to 100μg/ml for vemurafenib, from 1 to 1000ng/ml for dabrafenib, from 0.5 to 500ng/ml for cobimetinib and binimetinib, and from 0.75 to 250ng/ml for trametinib. At all concentrations the bias was within ±15% of the nominal concentrations and precision was ≤15%. All results were within the acceptance criteria of the EMA guidelines on method validation. This rapid, sensitive and specific UPLC-MS/MS method can perform simultaneous quantification of targeted therapies used in malignant melanoma and is usable for routine TDM.

    Topics: Azetidines; Benzimidazoles; Chromatography, High Pressure Liquid; Humans; Imidazoles; Indoles; Limit of Detection; Linear Models; Melanoma; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Tandem Mass Spectrometry; Vemurafenib

2017
Baseline β-catenin, programmed death-ligand 1 expression and tumour-infiltrating lymphocytes predict response and poor prognosis in BRAF inhibitor-treated melanoma patients.
    European journal of cancer (Oxford, England : 1990), 2017, Volume: 78

    The activation of oncogenic Wnt/β-catenin pathway in melanoma contributes to a lack of T-cell infiltration. Whether baseline β-catenin expression in the context of tumour-infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) overexpression correlates with prognosis of metastatic melanoma patients (MMPs) treated with mitogen-activated protein kinase, MAPK inhibitor (MAPKi) monotherapy, however, has not been fully clarified.. Sixty-four pre-treatment formalin-fixed and paraffin embedded melanoma samples from MMP treated with a BRAF inhibitor (n = 39) or BRAF and MEK inhibitors (n = 25) were assessed for presence of β-catenin, PD-L1, cluster of differentiation (CD)8, CD103 and forkhead box protein P3 (FOXP3) expression by immunohistochemistry, and results were correlated with clinical outcome. Quantitative assessment of mRNA transcripts associated with Wnt/β-catenin pathway and immune response was performed in 51 patients.. We found an inverse correlation between tumoural β-catenin expression and the level of CD8, CD103 or forkhead box protein P3 (FOXP3) positivity in the tumour microenvironment (TME). By multivariate analysis, PD-L1 <5% (odds ratio, OR 0.12, 95% confidence interval, CI 0.03-0.53, p = 0.005) and the presence of CD8+ T cells (OR 18.27, 95%CI 2.54-131.52, p = 0.004) were significantly associated with a higher probability of response to MAPKi monotherapy. Responding patients showed a significantly increased expression of mRNA transcripts associated with adaptive immunity and antigen presentation. By multivariate analysis, progression-free survival (PFS) (hazards ratio (HR) = 0.25 95%CI 0.10-0.61, p = 0.002) and overall survival (OS) (HR = 0.24 95%CI 0.09-0.67, p = 0.006) were longer in patients with high density of CD8+ T cells and β-catenin <10% than those without CD8+ T cells infiltration and β-catenin ≥10%.. Our findings provide evidence that in the context of MAPKi monotherapy, immune subsets in the (TME) and gene signature predict prognosis in MMPs.

    Topics: Adult; Aged; Aged, 80 and over; Antigens, CD; beta Catenin; CD8 Antigens; Female; Forkhead Transcription Factors; Humans; Imidazoles; Indoles; Integrin alpha Chains; Lymphocytes, Tumor-Infiltrating; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Prognosis; Programmed Cell Death 1 Receptor; Prospective Studies; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Treatment Outcome; Vemurafenib; Young Adult

2017
Identification of MAP kinase pathways as therapeutic targets in gallbladder carcinoma using targeted parallel sequencing.
    Oncotarget, 2017, May-30, Volume: 8, Issue:22

    The aim of this study was to profile somatic mutation spectrum in gallbladder cancers (GBCs), and determine the role of MAP kinase pathway in GBC by a series of in vitro and in vivo studies. We performed targeted massively parallel sequencing of DNA isolated from GBCs and matched blood from 14 GBC patients to search for mutations in 504 genes commonly altered in human cancers. We identified recurrent mutations enriched in several major signaling pathways including MAP kinase, Wnt/β-catenin and NF-κB pathways. Immunohistochemistry analysis further validated overactivation of MAP kinase and Wnt pathways in a panel of GBC samples. By treating GBC cells with MEK inhibitor trametinib, we found that trametinib not only dramatically inhibited the activity of MAPK/ERK pathway, but also blocked the Wnt/β-catenin signaling through decreasing β-catenin expression or suppressing nucleus translocation of β-catenin. Moreover, trametinib inhibited the proliferation of GBC cell in a dose- and time-dependent manner, induced GBC cell apoptosis, and inhibited GBC cell migration and invasion. Growth of xenograft tumors derived from GBC cell line NOZ in nude mice was also significantly inhibited by trametinib. Our data highlight the critical role of MAP kinase pathways in GBC pathogenesis, and may represent therapeutic targets for this cancer.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; DNA Mutational Analysis; Gallbladder Neoplasms; High-Throughput Nucleotide Sequencing; Humans; MAP Kinase Signaling System; Mice; Molecular Targeted Therapy; Mutation; NF-kappa B; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction; Tumor Stem Cell Assay; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

2017
BRAF-V600E mutant papillary craniopharyngioma dramatically responds to combination BRAF and MEK inhibitors.
    CNS oncology, 2017, Volume: 6, Issue:2

    We present a patient with BRAF-V600E mutant papillary craniopharyngioma successfully treated with combination BRAF (dabrafenib 150 mg twice daily) and MEK (trametinib 2 mg daily) inhibitors after her unresectable tumor proved refractory to radiation. Serial brain MRIs and PET revealed marked tumor reduction with gradual neurological improvement and permanent panhypopituitarism.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Craniopharyngioma; Female; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Pituitary Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2017
The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma.
    British journal of cancer, 2017, 05-23, Volume: 116, Issue:11

    Cholangiocarcinoma is an aggressive malignancy with limited therapeutic options. MEK inhibition and antiangiogenic therapies have individually shown modest activity in advanced cholangiocarcinoma, whereas dual inhibition of these pathways has not been previously evaluated. We evaluated the safety and efficacy of combination therapy with the oral VEGF receptor tyrosine kinase inhibitor pazopanib plus the MEK inhibitor trametinib in patients with advanced cholangiocarcinoma.. In this open-label, multicentre, single-arm trial, adults with advanced unresectable cholangiocarcinoma received pazopanib 800 mg daily and trametinib 2 mg daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) with secondary end points including overall survival (OS), response rate, and disease control rate (DCR).. A total of 25 patients were enrolled and had received a median of 2 prior systemic therapies (range 1-7). Median PFS was 3.6 months (95% CI: 2.7-5.1) and the 4-month PFS was 40% (95% CI: 24.7-64.6%). There was a trend towards increased 4-month PFS as compared with the prespecified null hypothesised 4-month PFS of 25%, but this difference did not reach statistical significance (P=0.063). The median survival was 6.4 months (95% CI: 4.3-10.2). The objective response rate was 5% (95% CI: 0.13-24.9%) and the DCR was 75% (95% CI: 51%, 91%). Grade 3/4 adverse events attributable to study drugs were observed in 14 (56%) and included thrombocytopenia, abnormal liver enzymes, rash, and hypertension.. Although the combination of pazopanib plus trametinib had acceptable toxicity with evidence of clinical activity, it did not achieve a statistically significant improvement in 4-month PFS over the prespecified null hypothesised 4-month PFS.

    Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Cholangiocarcinoma; Disease Progression; Disease-Free Survival; Drug Eruptions; Exanthema; Female; Humans; Hypertension; Indazoles; Male; MAP Kinase Kinase Kinases; Middle Aged; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Pyrimidinones; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Survival Rate; Thrombocytopenia

2017
IQGAP1 is an oncogenic target in canine melanoma.
    PloS one, 2017, Volume: 12, Issue:4

    Canine oral mucosal melanoma is an aggressive malignant neoplasm and is characterized by local infiltration and a high metastatic potential. The disease progression is similar to that of human oral melanomas. Whereas human cutaneous melanoma is primarily driven by activating mutations in Braf (60%) or Nras (20%), human mucosal melanoma harbors these mutations much less frequently. This makes therapeutic targeting and research modeling of the oral form potentially different from that of the cutaneous form in humans. Similarly, research has found only rare Nras mutations and no activating Braf mutations in canine oral melanomas, but they are still reliant on MAPK signaling. IQGAP1 is a signaling scaffold that regulates oncogenic ERK1/2 MAPK signaling in human Ras- and Raf- driven cancers, including melanomas. To investigate whether IQGAP1 is a potential target in canine melanoma, we examined the expression and localization of IQGAP1 in primary canine melanomas and canine oral melanoma cell lines obtained from the University of California-Davis. Using CRISPR/Cas9 knockout of IQGAP1, we examined effects on downstream ERK1/2 pathway activity and assayed proliferation of cell lines when treated with a peptide that blocks the interaction between IQGAP1 and ERK1/2. We observed that canine IQGAP1 is expressed and localizes to a similar extent in both human and canine melanoma by qPCR, Western blot, and immunofluorescence. Deletion of IQGAP1 reduces MAPK pathway activation in cell lines, similar to effects seen in human BrafV600E cell lines. Additionally, we demonstrated reduced proliferation when these cells are treated with a blocking peptide in vitro.

    Topics: Animals; Cell Line, Tumor; Cell Proliferation; CRISPR-Cas Systems; Dogs; Gene Knockout Techniques; Humans; Immunohistochemistry; MAP Kinase Signaling System; Melanoma; Mice; Microscopy, Fluorescence; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mouth Neoplasms; Mutation; Oncogenes; Phosphorylation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; ras GTPase-Activating Proteins

2017
Endometrial Cancers With Activating KRas Mutations Have Activated Estrogen Signaling and Paradoxical Response to MEK Inhibition.
    International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 2017, Volume: 27, Issue:5

    The aims of this study were to determine if activating KRas mutation alters estrogen signaling in endometrial cancer (EC) and to explore the potential therapeutic impact of these alterations.. The Cancer Genome Atlas was queried for changes in estrogen-regulated genes in EC based on KRas mutation status. In vitro studies were conducted to evaluate estrogen receptor α (ERα) phosphorylation changes and related kinase changes in KRas mutant EC cells. The resulting effect on response to MEK inhibition, using trametinib, was evaluated. Immunohistochemistry was performed on KRas mutant and wild-type EC tumors to test estrogen signaling differences.. KRas mutant tumors in The Cancer Genome Atlas showed decreased progesterone receptor expression (P = 0.047). Protein analysis in KRas mutant EC cells also showed decreased expression of ERα (P < 0.001) and progesterone receptor (P = 0.001). Although total ERα is decreased in KRas mutant cells, phospho-ERα S118 was increased compared with wild type. Treatment with trametinib in KRas mutant cells increased phospho-ERα S167 and increased expression of estrogen-regulated genes. While MEK inhibition blocked estradiol-stimulated phosphorylation of ERK1/2 and p90RSK in wild-type cells, phospho-ERK1/2 and phospho-p90RSK were substantially increased in KRas mutants. KRas mutant EC tumor specimens showed similar changes, with increased phospho-ERα S118 and phospho-ERα S167 compared with wild-type EC tumors.. MEK inhibition in KRas mutant cells results in activation of ER signaling and prevents the abrogation of signaling through ERK1/2 and p90RSK that is achieved in KRas wild-type EC cells. Combination therapy with MEK inhibition plus antiestrogen therapy may be necessary to improve response rates in patients with KRas mutant EC.

    Topics: Endometrial Neoplasms; Estradiol; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Receptors, Progesterone

2017
MEK inhibitors cobimetinib and trametinib, regressed a gemcitabine-resistant pancreatic-cancer patient-derived orthotopic xenograft (PDOX).
    Oncotarget, 2017, Jul-18, Volume: 8, Issue:29

    A pancreatic ductal adenocarcinoma (PDAC), obtained from a patient, was grown orthotopically in the pancreatic tail of nude mice to establish a patient-derived orthotopic (PDOX) model. Seven weeks after implantation, PDOX nude mice were divided into the following groups: untreated control (n = 7); gemcitabine (100 mg/kg, i.p., once a week for 2 weeks, n = 7); cobimetinib (5 mg/kg, p.o., 14 consecutive days, n = 7); trametinib (0.3 mg/kg, p.o., 14 consecutive days, n = 7); trabectedin (0.15 mg/kg, i.v., once a week for 2 weeks, n = 7); temozolomide (25 mg/kg, p.o., 14 consecutive days, n = 7); carfilzomib (2 mg/kg, i.v., twice a week for 2 weeks, n = 7); bortezomib (1 mg/kg, i.v., twice a week for 2 weeks, n = 7); MK-1775 (20 mg/kg, p.o., 14 consecutive days, n = 7); BEZ-235 (45 mg/kg, p.o., 14 consecutive days, n = 7); vorinostat (50 mg/kg, i.p., 14 consecutive days, n = 7). Only the MEK inhibitors, cobimetinib and trametinib, regressed tumor growth, and they were more significantly effective than other therapies (p < 0.0001, respectively), thereby demonstrating the precision of the PDOX models of PDAC and its potential for individualizing pancreatic-cancer therapy.

    Topics: Animals; Antineoplastic Agents; Azetidines; Cell Line, Tumor; Deoxycytidine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Gemcitabine; Humans; Mice; Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2017
Synergistic effect of MEK inhibitor and metformin combination in low grade serous ovarian cancer.
    Gynecologic oncology, 2017, Volume: 146, Issue:2

    Low-grade serous ovarian cancer (LGSOC) constitutes 5-8% of epithelial ovarian cancers and is refractory to chemotherapy. We and others have shown metformin to cause significant growth inhibition in high-grade ovarian cancer both in vitro and in vivo. Here, we aimed to analyze if metformin was effective in inhibiting proliferation of LGSOC alone and in combination with MEK inhibitor.. Three LGSOC lines (VOA1056, VOA1312 and VOA5646) were treated with metformin, trametinib or 2-deoxyglucose (2DG) alone or in combination with metformin. Proliferation was measured by MTT assay over a period of four days. Protein expression was measured by western blotting. Seahorse Analyzer was used to measure effect of metformin on glycolysis and mitochondrial respiration.. All LGSOC cell lines showed significant inhibition with metformin in a dose- and time-dependent manner. Trametinib significantly inhibited the growth of Ras mutated LGSOC lines (VOA1312 and VOA1056), while VOA5646 cells without RAS mutation did not show any response. Metformin and trametinib combination showed synergistic inhibition of RAS mutated VOA1312 and VOA1056 cells, but not for non-Ras mutated VOA5646 cells. Metformin and trametinib increased phosphorylated AMPK expression in LGSOC lines with combination showing stronger expression. Trametinib decreased 42/44 mitogen activated kinase phosphorylation in all cell lines, while metformin and combination had no significant effect. 2-DG significantly inhibited glycolysis in all LGSOC lines and combination with metformin showed synergistic inhibitory effect.. Metformin alone or in combination with MEK and glycolytic inhibitors may be a potential therapy for LGSOC, a cancer that is indolent but chemo-resistant.

    Topics: AMP-Activated Protein Kinases; Antimetabolites; Blotting, Western; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Proliferation; Deoxyglucose; Drug Synergism; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Metformin; Neoplasm Grading; Neoplasms, Cystic, Mucinous, and Serous; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; ras Proteins; Signal Transduction

2017
MEK and PI3K catalytic activity as predictor of the response to molecularly targeted agents in triple-negative breast cancer.
    Biochemical and biophysical research communications, 2017, 08-05, Volume: 489, Issue:4

    Hyper-activation of the MAPK and PI3K-AKT pathways is linked to tumour progression in triple-negative breast cancer (TNBC). However, clinically effective predictive markers for drugs targeted against protein kinases involved in these pathways have not been identified. We investigated the ability of MEK and PI3K catalytic activity to predict sensitivity to trametinib and wortmannin in TNBC. MEK and PI3K activities correlated strongly with each other only in cell lines showing wortmannin-specific sensitivity, as shown by a linear regression curve (R = 0.951). Accordingly, we created a new parameter that distinguishes trametinib and wortmannin sensitivity in vitro and in vivo. Our findings suggest that the catalytic activities of MEK and PI3K might predict the response of TNBC to trametinib and wortmannin.

    Topics: Androstadienes; Animals; Antineoplastic Agents; Biocatalysis; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyridones; Pyrimidinones; Structure-Activity Relationship; Triple Negative Breast Neoplasms; Tumor Cells, Cultured; Wortmannin

2017
Successful re-challenge with anti-BRAF and anti-MEK in a patient with symptomatic melanoma flare.
    European journal of cancer (Oxford, England : 1990), 2017, Volume: 82

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Male; Melanoma; Mitogen-Activated Protein Kinase Kinases; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Remission Induction; Skin Neoplasms; Treatment Outcome

2017
Possible macrophage activation in melanoma patients receiving combined kinase inhibitor therapy following anti-PD-1 therapy: a cytokine profiling study of two cases.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2017, 10-01, Volume: 28, Issue:10

    Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cytokines; Female; Humans; Imidazoles; Indoles; Macrophage Activation; Male; Melanoma; Middle Aged; Nivolumab; Oximes; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2017
Targeting Adenosine in BRAF-Mutant Melanoma Reduces Tumor Growth and Metastasis.
    Cancer research, 2017, 09-01, Volume: 77, Issue:17

    Increasing evidence exists for the role of immunosuppressive adenosine in promoting tumor growth and spread in a number of cancer types, resulting in poor clinical outcomes. In this study, we assessed whether the CD73-adenosinergic pathway is active in melanoma patients and whether adenosine restricts the efficacy of clinically approved targeted therapies for commonly mutated BRAF

    Topics: 5'-Nucleotidase; Adenosine; Animals; Drug Therapy, Combination; GPI-Linked Proteins; Humans; Imidazoles; Lung Neoplasms; MAP Kinase Kinase 1; Melanoma; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Targeted Therapy; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Receptor, Adenosine A2A; Skin Neoplasms

2017
Lack of growth inhibitory synergism with combined MAPK/PI3K inhibition in preclinical models of pancreatic cancer.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2017, 11-01, Volume: 28, Issue:11

    Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Growth Processes; Drug Synergism; Heterocyclic Compounds, 3-Ring; Humans; MAP Kinase Kinase Kinases; Morpholines; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Triazines

2017
Small molecule-based inhibition of MEK1/2 proteins dampens inflammatory responses to malaria, reduces parasite load, and mitigates pathogenic outcomes.
    The Journal of biological chemistry, 2017, 08-18, Volume: 292, Issue:33

    Malaria infections cause several systemic and severe single- or multi-organ pathologies, killing hundreds of thousands of people annually. Considering the existing widespread resistance of malaria parasites to anti-parasitic drugs and their high propensity to develop drug resistance, alternative strategies are required to manage malaria infections. Because malaria is a host immune response-driven disease, one approach is based on gaining a detailed understanding of the molecular and cellular processes that modulate malaria-induced innate and adaptive immune responses. Here, using a mouse cerebral malaria model and small-molecule inhibitors, we demonstrate that inhibiting MEK1/2, the upstream kinases of ERK1/2 signaling, alters multifactorial components of the innate and adaptive immune responses, controls parasitemia, and blocks pathogenesis. Specifically, MEK1/2 inhibitor treatment up-regulated B1 cell expansion, IgM production, phagocytic receptor expression, and phagocytic activity, enhancing parasite clearance by macrophages and neutrophils. Further, the MEK1/2 inhibitor treatment down-regulated pathogenic pro-inflammatory and helper T cell 1 (Th1) responses and up-regulated beneficial anti-inflammatory cytokine responses and Th2 responses. These inhibitor effects resulted in reduced granzyme B expression by T cells, chemokine and intracellular cell adhesion molecule 1 (ICAM-1) expression in the brain, and chemokine receptor expression by both myeloid and T cells. These bimodal effects of the MEK1/2 inhibitor treatment on immune responses contributed to decreased parasite biomass, organ inflammation, and immune cell recruitment, preventing tissue damage and death. In summary, we have identified several previously unrecognized immune regulatory processes through which a MEK1/2 inhibitor approach controls malaria parasitemia and mitigates pathogenic effects on host organs.

    Topics: Adaptive Immunity; Animals; Antimalarials; Bone Marrow Cells; Cells, Cultured; Coculture Techniques; Dendritic Cells; Female; Flavonoids; Immunity, Innate; Killer Cells, Natural; Malaria, Cerebral; Malaria, Falciparum; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mice, Inbred C57BL; Parasite Load; Parasitemia; Phagocytosis; Plasmodium falciparum; Protein Kinase Inhibitors; Protozoan Proteins; Pyridones; Pyrimidinones; Survival Analysis

2017
Melanocytic lesion evolution patterns with targeted therapies and immunotherapies for advanced metastatic melanoma: An observational study.
    The Australasian journal of dermatology, 2017, Volume: 58, Issue:4

    Various cutaneous side-effects have been reported with anti-melanoma systemic therapies. This study investigated the changes in melanocytic lesion pigmentation in patients on four different therapies.. We analysed the serial dermatoscopic photographs of atypical melanocytic lesions taken from patients with advanced metastatic melanoma on four different systemic therapies (selective BRAF-inhibitor monotherapy, dabrafenib combined with trametinib [D&T], anti-programmed cell death protein 1 [anti-PD1] therapies, and anti-PD1 combined with ipilimumab) seen from February 2013 to May 2016. We compared these changes with the melanocytic lesions of 10 control patients.. In the control group, 19% of naevi lightened, 64% did not change and 17% darkened. Only the BRAF inhibitor group showed more darkened lesions than controls (37%, P < 0.001). Meanwhile, there were more lightened naevi in the D&T therapy group (86%, P < 0.001) as well as the anti-PD1 and ipilimumab groups (59%, P < 0.001) than controls. Patients on anti-PD1 monotherapy had more lightened (49%) and fewer darkened naevi (9%) than controls, but differences were not significant.. Our study showed that different anti-melanoma systemic therapies have different effects on the pigmentation of melanocytic lesions. BRAF inhibitor may have the propensity to cause darkening while D&T therapy and anti-PD1 caused lightening compared with controls. The findings emphasise the importance of regular dermatological monitoring in specialised clinics for patients on anti-melanoma systemic therapy. Clinicians should expect changes in the global pigmentation of melanocytic lesions but be suspicious of lesions with structural changes.

    Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Dermoscopy; Female; Humans; Imidazoles; Ipilimumab; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Nivolumab; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Skin Pigmentation

2017
Clinical and Morphologic Characteristics of MEK Inhibitor-Associated Retinopathy: Differences from Central Serous Chorioretinopathy.
    Ophthalmology, 2017, Volume: 124, Issue:12

    To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking mitogen-activated protein kinase kinase (MEK) inhibitors.. A total of 313 fluid foci in 50 eyes of 25 patients receiving MEK inhibitors for treatment of their metastatic cancer, who had evidence of serous retinal detachments confirmed by optical coherence tomography (OCT).. Single-center, retrospective cohort study.. Clinical examination and OCT were used to evaluate MEK inhibitor-associated subretinal fluid. The morphology, distribution, and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation, and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate interobserver findings and compare choroidal thickness and visual acuity at each time point.. Comparison of OCT characteristics of retinal abnormalities at baseline to fluid accumulation.. The majority of patients had fluid foci that were bilateral (92%) and multifocal (77%) and at least 1 focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into 4 morphologies, as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy, and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than 2 Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation, and fluid resolution). A strong positive interobserver correlation was obtained for choroidal thickness measurements (r = 0.97, P < 0.0001) and grading of foci morphology (r = 0.97, P < 0.0001).. The subretinal fluid foci associated with MEK inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK inhibitors did not cause irreversible loss of vision or serious eye damage.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Azetidines; Benzimidazoles; Central Serous Chorioretinopathy; Female; Fluorescein Angiography; Humans; Male; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Retinal Detachment; Retrospective Studies; Subretinal Fluid; Tomography, Optical Coherence; Visual Acuity; Young Adult

2017
Synthetic lethal short hairpin RNA screening reveals that ring finger protein 183 confers resistance to trametinib in colorectal cancer cells.
    Chinese journal of cancer, 2017, Jul-31, Volume: 36, Issue:1

    The mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor trametinib has shown promising therapeutic effects on melanoma, but its efficacy on colorectal cancer (CRC) is limited. Synthetic lethality arises with a combination of two or more separate gene mutations that causes cell death, whereas individual mutations keep cells alive. This study aimed to identify the genes responsible for resistance to trametinib in CRC cells, using a synthetic lethal short hairpin RNA (shRNA) screening approach.. We infected HT29 cells with a pooled lentiviral shRNA library and applied next-generation sequencing to identify shRNAs with reduced abundance after 8-day treatment of 20 nmol/L trametinib. HCT116 and HT29 cells were used in validation studies. Stable ring finger protein 183 (RNF183)-overexpressing cell lines were generated by pcDNA4-myc/his-RNF183 transfection. Stable RNF183-knockdown cell lines were generated by infection of lentiviruses that express RNF183 shRNA, and small interference RNA (siRNA) was used to knock down RNF183 transiently. Quantitative real-time PCR was used to determine the mRNA expression. Western blotting, immunohistochemical analysis, and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the protein abundance. MTT assay, colony formation assay, and subcutaneous xenograft tumor growth model were used to evaluate cell proliferation.. In the primary screening, we found that the abundance of RNF183 shRNA was markedly reduced after treatment with trametinib. Trametinib induced the expression of RNF183, which conferred resistance to drug-induced cell growth repression and apoptotic and non-apoptotic cell deaths. Moreover, interleukin-8 (IL-8) was a downstream gene of RNF183 and was required for the function of RNF183 in facilitating cell growth. Additionally, elevated RNF183 expression partly reduced the inhibitory effect of trametinib on IL-8 expression. Finally, xenograft tumor model showed the synergism of RNF183 knockdown and trametinib in repressing the growth of CRC cells in vivo.. The RNF183-IL-8 axis is responsible for the resistance of CRC cells to the MEK1/2 inhibitor trametinib and may serve as a candidate target for combined therapy for CRC.

    Topics: Animals; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; HT29 Cells; Humans; Mice; Pyridones; Pyrimidinones; RNA, Small Interfering; Synthetic Lethal Mutations; Ubiquitin-Protein Ligases; Xenograft Model Antitumor Assays

2017
Choroidal Neovascularization in Multifocal Choroiditis after Dabrafenib and Trametinib.
    European journal of ophthalmology, 2017, Nov-08, Volume: 27, Issue:6

    To describe a case of bilateral choroidal neovascularization (CNV) in multifocal choroiditis (MFC) associated with dabrafenib and trametinib chemotherapy for metastatic melanoma.. We present a case of a 57-year-old man with MFC who underwent combination therapy with dabrafenib plus trametinib for metastatic melanoma. The patient presented to our ophthalmology department complaining of bilateral vision loss of 2 days' duration. He underwent multimodal imaging showing a MFC reactivation complicated by bilateral CNV. The patient underwent 3 ranibizumab injections in the right eye and 7 ranibizumab injections in the left eye. Anatomical and functional improvement has been observed.. This report emphasizes the importance of strict ophthalmologic follow-up in patients with metastatic melanoma treated with dabrafenib plus trametinib since rare severe ocular toxicities can occur, especially in patients with a history of uveitis.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Choroidal Neovascularization; Choroiditis; Fluorescein Angiography; Humans; Imidazoles; Male; Melanoma; Middle Aged; Multifocal Choroiditis; Multimodal Imaging; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Tomography, Optical Coherence

2017
Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
    Nature, 2017, 08-10, Volume: 548, Issue:7666

    Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.

    Topics: Animals; Cell Line, Tumor; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Indoles; MAP Kinase Signaling System; Melanoma; Mice; Mitogen-Activated Protein Kinase Kinases; Mutation; Neurofibromatosis 1; NIH 3T3 Cells; Oncogene Protein p21(ras); Protein Multimerization; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib; Xenograft Model Antitumor Assays

2017
Intermittent Dosing of Dabrafenib and Trametinib in Metastatic BRAF
    Thyroid : official journal of the American Thyroid Association, 2017, Volume: 27, Issue:9

    A multi-institutional, randomized phase II trial of continuous dosing of dabrafenib with or without trametinib is ongoing in metastatic thyroid cancer. Preclinical evidence and emerging clinical experience in other cancers support evaluating intermittent dosing of these two agents to achieve more durable response, while being better tolerated and more cost effective.. Two consecutive patients with symptomatic, metastatic radioactive iodine-resistant BRAF. Both patients showed rapid clinical improvement upon starting the regimen. They also noted improved tolerance of treatment upon transitioning to the intermittent dosing schedule. They continue to show evidence of antitumor activity 27 and 18 months respectively from the start of treatment and 15 and 13 months respectively from the start of the first break using intermittent dosing.. Achieving durable palliation in these consecutive patients supports evaluating the intermittent dosing schedule of dabrafenib and trametinib in BRAF

    Topics: Aged, 80 and over; Amino Acid Substitution; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Papillary; Drug Administration Schedule; Drug Monitoring; Female; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Palliative Care; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Thyroid Cancer, Papillary; Thyroid Neoplasms; Treatment Outcome

2017
Ocular toxicity due to Trametinib and Dabrafenib.
    BMC ophthalmology, 2017, Aug-17, Volume: 17, Issue:1

    To report a case of uveitis and neuroretinal detachment in a patient treated with Trametinib and Dabrafenib due to metastatic cutaneous melanoma stage IV.. We evaluated slit lamp examination, fundoscopy, optical coherence tomography, fluorescein and indocyanine green angiography in a 66 years old man suffering visual loss. Fundoscopy showed serous neuroretinal detachment of the fovea accompanied with white spots surrounding the fovea in both eyes. Although therapy with Trametinib and Dabrafenib was stopped uveitis anterior was seen 2 weeks later. After a year, the therapy was started again and the serous neuroretinal detachment appeared once more, however without inflammatory reaction of the anterior chamber.. Patients treated with Trametinib and Dabrafenib should undergo consecutive eye examinations from the beginning of the therapy.

    Topics: Aged; Antineoplastic Agents; Humans; Imidazoles; Male; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Retinal Detachment; Uveitis

2017
Exogenous growth factors bFGF, EGF and HGF do not influence viability and phenotype of V600EBRAF melanoma cells and their response to vemurafenib and trametinib in vitro.
    PloS one, 2017, Volume: 12, Issue:8

    It has been shown that the response of V600EBRAF melanoma cells to targeted therapeutics is affected by growth factors. We have investigated the influence of three different growth factors, bFGF, EGF and HGF used either alone or in combination, on the response of V600EBRAF melanoma cell populations established from surgical specimens to vemurafenib and trametinib, targeting V600EBRAF and MEK1/2, respectively. We report that proliferation and phenotype of V600EBRAF melanoma cell populations were not detectably influenced by exogenous growth factors. Neither cell distribution in cell cycle and CCND1 expression nor activity of signaling pathways crucial for melanoma development and maintenance, including the RAF/MEK/ERK pathway, WNT/β-catenin pathway and NF-κB signaling, were affected by the presence of different growth factors. We furthermore show that vemurafenib and trametinib abrogated the activity of ERK1/2, arrested cells in G0/G1 cell cycle phase, triggered apoptosis, induced changes in the expression of CXCL8, CCND1 and CTGF and the frequency of Ki-67high and CD271high cells. These effects were, however, similar in the presence of different growth factors. Interestingly, comparable results were also obtained for melanoma cells grown without exogenous growth factors bFGF, EGF and HGF for a period as long as 4 months prior the drug treatment. We conclude that the composition or lack of exogenous growth factors bFGF, EGF and HGF do not markedly influence viability and phenotype of V600EBRAF melanoma cells and their response to vemurafenib and trametinib in vitro. Our results question the necessity of these growth factors in the medium that is used for culturing V600EBRAF melanoma cells.

    Topics: Antineoplastic Agents; Blotting, Western; Epidermal Growth Factor; Fibroblast Growth Factor 2; Flow Cytometry; Hepatocyte Growth Factor; Humans; Immunophenotyping; In Vitro Techniques; Indoles; Melanoma; Microscopy, Fluorescence; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Tumor Cells, Cultured; Vemurafenib

2017
Donor-Derived Metastatic Melanoma and Checkpoint Inhibition.
    Transplantation proceedings, 2017, Volume: 49, Issue:7

    Donor-derived malignancy, particularly melanoma, is a rare but known complication of organ transplantation. Here we describe a case of metastatic melanoma in a deceased-donor kidney transplant recipient. After diagnosis, the patient was successfully treated with cessation of immunosuppression, explantation of the renal allograft, and novel melanoma therapies, including the mutation-targeted agents dabrafenib and trametinib and the immune checkpoint inhibitor nivolumab. These 2 new classes of melanoma therapy have revolutionized the course of metastatic melanoma, altering it from one of nearly certain mortality to one of potential cure. This case reviews the mechanisms of action of these therapies and reports our experience with them in the rare setting of donor-derived melanoma in a dialysis-dependent patient.

    Topics: Allografts; Antibodies, Monoclonal; Antineoplastic Agents; Checkpoint Kinase 1; Checkpoint Kinase 2; Humans; Imidazoles; Kidney; Kidney Neoplasms; Kidney Transplantation; Liver Neoplasms; Lung Neoplasms; Male; Melanoma; Middle Aged; Nivolumab; Oximes; Pyridones; Pyrimidinones; Tissue Donors

2017
Recurrent papillary craniopharyngioma with BRAFV600E mutation treated with neoadjuvant-targeted therapy.
    Acta neurochirurgica, 2017, Volume: 159, Issue:11

    Craniopharyngiomas are histologically benign but locally aggressive tumors in the sellar region that may cause devastating neurological and endocrine deficits. They tend to recur following surgery with high morbidity; hence, postoperative radiotherapy is recommended following sub-total resection. BRAFV600E mutation is the principal oncogenic driver in the papillary variant of craniopharyngiomas. Recently, a dramatic tumor reduction has been reported in a patient with BRAFV600E mutated, multiply recurrent papillary craniopharyngioma using a combination therapy of BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Here, we report on near-radical reduction of a growing residual BRAFV600E craniopharyngioma using the same neoadjuvant therapy.

    Topics: Aged; Craniopharyngioma; Humans; Imidazoles; Male; Molecular Targeted Therapy; Mutation; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Oximes; Pituitary Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sella Turcica

2017
Fibroblast growth factor-2-mediated FGFR/Erk signaling supports maintenance of cancer stem-like cells in esophageal squamous cell carcinoma.
    Carcinogenesis, 2017, 10-26, Volume: 38, Issue:11

    In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT). Conversely, the FGFR inhibitor, AZD4547, sharply diminishes CSCs via induction of mesenchymal-epithelial transition. Further experiments revealed that MAPK/Erk kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is crucial for FGF-2-mediated CSC regulation. Pharmacological inhibition of FGF receptor (FGFR)-mediated signaling via AZD4547 did not affect CSCs in Ras mutated cells, implying that Mek/Erk pathway, downstream of FGFR signaling, might be an important regulator of CSCs. Indeed, the Mek inhibitor, trametinib, efficiently suppressed ESCC CSCs even in the context of Ras mutation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Taken together, these findings indicate that FGF-2 is an essential factor regulating CSCs via Mek/Erk signaling in ESCC. Additionally, inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.

    Topics: Benzamides; Carcinoma, Squamous Cell; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Extracellular Signal-Regulated MAP Kinases; Fibroblast Growth Factor 2; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Neoplastic Stem Cells; Piperazines; Pyrazoles; Pyridones; Pyrimidinones; Receptors, Fibroblast Growth Factor; Signal Transduction

2017
Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer.
    Nature communications, 2017, 09-19, Volume: 8, Issue:1

    The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo. This effect is dependent upon increased downstream p38/JNK pathway activation. Taken together, our data suggest that although Ras/MAPK pathway inhibition can increase tumor immunogenicity, the negative impact on T-cell activity is functionally important. This undesirable impact is effectively prevented by combination with T-cell immune agonist immunotherapies resulting in superior therapeutic efficacy.MEK inhibition in breast cancer is associated with increased tumour infiltrating lymphocytes (TILs), however, MAPK activity is required for T cells function. Here the authors show that TILs activity following MEK inhibition can be enhanced by agonist immunotherapy resulting in synergic therapeutic effects.

    Topics: 4-1BB Ligand; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Humans; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Mammary Neoplasms, Animal; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Mice; OX40 Ligand; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; T-Lymphocyte Subsets; T-Lymphocytes; Triple Negative Breast Neoplasms

2017
A large metastatic intramammary lesion of an occult melanoma.
    Annali italiani di chirurgia, 2017, Volume: 88

    Malignant melanomas presenting with unknown primaries are uncommon. In the majority of cases metastases of occult melanoma were detected in skin or in lymph nodes. Melanoma can rarely occur as a primary or metastatic intramammary tumor.. We report the case of a 58-year-old Caucasian woman who came to our department with a voluminous mass in her right breast. Histopathological examination found metastasis of epithelioid melanoma with unknown primary lesion. Our patient underwent a radical enlarged mastectomy, but due to the extension a radical removal was not possible.. In 2.2% of cases, melanoma may present with a metastasis without an identifiable primary lesion; this case should be considered a stage IV melanoma (Tx; N1; M1) due to the extension of the lesion and the infiltration of adjacent structures.. In literature, the presence of a breast metastasis of melanoma with unknown primary origin was reported just in one case. The execution of histopathological analysis is mandatory for a correct differential diagnosis with primary carcinoma of the breast. Palliative metastasectomy should be discussed with multidisciplinary melanoma board.. Breast metastases, Metastatic melanoma, Unknown primary site.. Il melanoma maligno, nel 2.2% dei casi, si presenta in forma metastatica con localizzazione primaria non identificabile, si parla in questi casi di metastasi da melanoma primitivo occulto. Le metastasi di melanoma sono localizzate più frequentemente a livello cutaneo e linfonodale, mentre la presenza di metastasi mammarie è poco frequente. In letteratura è riportato un solo caso di metastasi intramammarie da melanoma primitivo occulto, in questo lavoro ne presentiamo un nuovo caso. Si tratta di una donna caucasica di 58 anni che è giunta alla nostra attenzione per una voluminosa massa a livello della mammella destra. L’esame istologico della lesione ha diagnosticato la presenza di metastasi mammaria da melanoma cutaneo. La paziente è stata quindi sottoposta ad un accurato esame dermatologico, oftalmologico, pneumologico e gastroenterologico ma non è stata identificata la lesione primitiva. Si tratta di un caso molto particolare e di difficile gestione ed inquadramento terapeutico per le dimensioni della massa e l’estesa infiltrazione alla parete toracica anteriore. La paziente è stata sottoposta a mastectomia radicale allargata, ma a causa dell’estensione della lesione non è stata possibile un’escissione radicale. Sebbene la stadiazione del melanoma occulto sia difficile a causa dell’impossibilità di determinare se si tratti di metastasi regionali o a distanza, questo caso dovrebbe essere considerato uno stadio IV (Tx; N1; M1) per l’estensione e l’infiltrazione delle strutture adiacenti. Nei casi di metastasi intramammarie l’esame istopatologico è dirimente per una corretta diagnosi differenziale con il carcinoma mammario primitivo. La mastectomia palliativa dovrebbe essere attentamente valutata con un team multidisciplinare per la cura del melanoma.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Combined Modality Therapy; Diagnosis, Differential; Female; Humans; Imidazoles; Mastectomy; Melanoma; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms, Unknown Primary; Oximes; Palliative Care; Pyridones; Pyrimidinones

2017
Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers.
    PloS one, 2017, Volume: 12, Issue:9

    Pancreatic cancer is an increasing cause of cancer related death worldwide. KRAS is the dominant oncogene in this cancer type and molecular rationale would indicate, that inhibitors of the downstream target MEK could be appropriate targeted agents, but clinical trials have failed so far to achieve statistically significant benefit in unselected patients. We aimed to identify predictive molecular biomarkers that can help to define subgroups where MEK inhibitors might be beneficial alone or in combination. Next-generation sequencing data of 50 genes in three pancreatic cancer cell lines (MiaPaCa2, BxPC3 and Panc1) were analyzed and compared to the molecular profile of 138 clinical pancreatic cancer samples to identify the molecular subtypes of pancreatic cancer these cell lines represent. Luminescent cell viability assay was used to determine the sensitivity of cell lines to kinase inhibitors. Western blot was used to analyze the pathway activity of the examined cell lines. According to our cell viability and pathway activity data on these model cell lines only cells harboring the rare G12C KRAS mutation and low EGFR expression are sensitive to single MEK inhibitor (trametinib) treatment. The common G12D KRAS mutation leads to elevated baseline Akt activity, thus treatment with single MEK inhibitors fails. However, combination of MEK and Akt inhibitors are synergistic in this case. In case of wild-type KRAS and high EGFR expression MEK inhibitor induced Akt phosphorylation leads to trametinib resistance which necessitates for MEK and EGFR or Akt inhibitor combination treatment. In all we provide strong preclinical rational and possible molecular mechanism to revisit MEK inhibitor therapy in pancreatic cancer in both monotherapy and combination, based on molecular profile analysis of pancreatic cancer samples and cell lines. According to our most remarkable finding, a small subgroup of patients with G12C KRAS mutation may still benefit from MEK inhibitor monotherapy.

    Topics: Cell Line, Tumor; ErbB Receptors; Genes, ras; Humans; MAP Kinase Kinase Kinases; Mutation; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction

2017
The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients.
    European journal of cancer (Oxford, England : 1990), 2017, Volume: 86

    The spectacular outcomes of the phase III trials regarding nivolumab versus ipilimumab in fully resected stage IIIB/C-IV and of the combination of dabrafenib (D) plus trametinib (T) in BRAF-mutant stage III patients demonstrate that effective treatments in advanced melanoma are also highly effective in the adjuvant setting. In 2016, an overall survival benefit with adjuvant high-dose ipilimumab was demonstrated, and the European Organisation for Research and Treatment of Cancer trial 1325 comparing pembrolizumab versus placebo will complete the picture in the early 2018. Toxicity profiles are in line with the experience in advanced melanoma, i.e. favourable for the anti-PD1 agents and for D + T and problematic for ipilimumab. The 2017 outcomes are practice changing and put an end to the use of interferon (IFN) and ipilimumab. In countries with only access to IFN, its use can be restricted to patients with ulcerated melanoma, based on the individual patient data meta-analysis recently published. Because of the results of the Melanoma Sentinel Lymph node Trial-2 (MSLT-2) trial, completion lymph node dissection (CLND) will decrease sharply, leading to a lack of optimal prognostic information. Prognosis in sentinel node-positive stage IIIA/B patients is extremely heterogeneous with 5-year survival rates varying from 90% to 40% and depends mostly on the number of positive nodes identified by CLND. This information is crucial for clinical decision-making. How to guarantee optimal staging information needs to be discussed urgently. Further improvements of adjuvant therapies will have to address all these questions as well as the exploration of neoadjuvant use of active drugs and combination approaches. Important paradigm shifts in the management of high-risk melanoma patients are upon us.

    Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Decision-Making; Evidence-Based Medicine; Humans; Imidazoles; Interferons; Ipilimumab; Melanoma; Neoadjuvant Therapy; Neoplasm Staging; Oximes; Patient Selection; Practice Patterns, Physicians'; Predictive Value of Tests; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Risk Factors; Skin Neoplasms; Time Factors; Treatment Outcome

2017
Dabrafenib and trametinib in BRAFV600E mutated glioma.
    CNS oncology, 2017, Volume: 6, Issue:4

    BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib.

    Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Glioma; Humans; Imidazoles; Middle Aged; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2017
Silencing FLI or targeting CD13/ANPEP lead to dephosphorylation of EPHA2, a mediator of BRAF inhibitor resistance, and induce growth arrest or apoptosis in melanoma cells.
    Cell death & disease, 2017, 08-31, Volume: 8, Issue:8

    A majority of patients with BRAF-mutated metastatic melanoma respond to therapy with BRAF inhibitors (BRAFi), but relapses are common owing to acquired resistance. To unravel BRAFi resistance mechanisms we have performed gene expression and mass spectrometry based proteome profiling of the sensitive parental A375 BRAF V600E-mutated human melanoma cell line and of daughter cell lines with induced BRAFi resistance. Increased expression of two novel resistance candidates, aminopeptidase-N (CD13/ANPEP) and ETS transcription factor FLI1 was observed in the BRAFi-resistant daughter cell lines. In addition, increased levels of the previously reported resistance mediators, receptor tyrosine kinase ephrine receptor A2 (EPHA2) and the hepatocyte growth factor receptor MET were also identified. The expression of these proteins was assessed in matched tumor samples from melanoma patients obtained before BRAFi and after disease progression. MET was overexpressed in all progression samples while the expression of the other candidates varied between the individual patients. Targeting CD13/ANPEP by a blocking antibody induced apoptosis in both parental A375- and BRAFi-resistant daughter cells as well as in melanoma cells with intrinsic BRAFi resistance and led to dephosphorylation of EPHA2 on S897, previously demonstrated to cause inhibition of the migratory capacity. AKT and RSK, both reported to induce EPHA2 S897 phosphorylation, were also dephosphorylated after inhibition of CD13/ANPEP. FLI1 silencing also caused decreases in EPHA2 S897 phosphorylation and in total MET protein expression. In addition, silencing of FLI1 sensitized the resistant cells to BRAFi. Furthermore, we show that BRAFi in combination with the multi kinase inhibitor dasatinib can abrogate BRAFi resistance and decrease both EPHA2 S897 phosphorylation and total FLI1 protein expression. This is the first report presenting CD13/ANPEP and FLI1 as important mediators of resistance to BRAF inhibition with potential as drug targets in BRAFi refractory melanoma.

    Topics: Antineoplastic Agents; Apoptosis; CD13 Antigens; Cell Cycle Checkpoints; Cell Line, Tumor; Dasatinib; Drug Resistance, Neoplasm; Ephrin-A2; Gene Expression Regulation, Neoplastic; Humans; Indoles; Melanoma; Microfilament Proteins; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Pyridones; Pyrimidinones; Receptor, EphA2; Receptors, Cytoplasmic and Nuclear; Ribosomal Protein S6 Kinases, 90-kDa; RNA, Small Interfering; Signal Transduction; Skin Neoplasms; Sulfonamides; Trans-Activators; Vemurafenib

2017
The MEK Inhibitors Trametinib and Cobimetinib Induce a Type I Interferon Response in Human Keratinocytes.
    International journal of molecular sciences, 2017, Oct-24, Volume: 18, Issue:10

    Mitogen-activated protein kinase kinases (MEK) 1 and 2 have crucial roles in tumorigenesis, cell proliferation, and protection from apoptosis, and their inhibition is therefore an attractive therapeutic strategy in cancer. Orally available and highly selective MEK inhibitors have been developed and assessed in numerous clinical trials, either alone or in combination with cytotoxic chemotherapy and/or other targeted agents. Of note, a complex picture of class-specific adverse effects associates with these drugs, frequently including inflammatory skin rash. Here, we investigated the response of normal human keratinocytes to the MEK inhibitors trametinib and cobimetinib, alone and in combination with the v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors dabrafenib and vemurafenib, in terms of signal transduction and de novo gene expression. MEK inhibitors triggered enhanced expression of interferon regulatory factor 1 (IRF1) and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and up-regulated the keratinocyte-specific type I interferon κ (IFN-κ), the anti-viral effectors interferon-induced tetratricopeptide repeats (IFIT) 1 and 2, and the pro-inflammatory chemokine (C-C motif) ligand 2 (CCL2) and the C-X-C motif chemokine 10 (CXCL10), both at the mRNA and protein level. Impairment of IRF1 expression, or abrogation of STAT1 phosphorylation due to

    Topics: Azetidines; Cell Line; Chemokine CCL2; Chemokine CXCL10; Gene Expression; Humans; Interferon Regulatory Factor-1; Interferon Type I; Interferon-Induced Helicase, IFIH1; Keratinocytes; MAP Kinase Kinase Kinases; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; RNA Interference; RNA, Small Interfering; Signal Transduction; STAT1 Transcription Factor

2017
A comparative study of the cutaneous side effects between BRAF monotherapy and BRAF/MEK inhibitor combination therapy in patients with advanced melanoma: a single-centre experience.
    European journal of dermatology : EJD, 2017, Oct-01, Volume: 27, Issue:5

    Patients with advanced melanoma have a poor prognosis. Since the discovery of BRAF mutations in cutaneous melanoma, new pharmacological agents have been developed to inhibit this target. Although the survival of patients with advanced melanoma has improved with BRAF inhibitors, the emergence of drug resistance and the high incidence of cutaneous side effects represent important limitations. The aim of our study was to compare the incidence of cutaneous side effects between BRAF inhibitor monotherapy and BRAF and MEK inhibitor combination therapy in our cohort of patients. This study was a longitudinal prospective observational study. The study population comprised 83 patients with advanced cutaneous melanoma presenting with BRAF V600 mutation. The inclusion criteria included: age above 18 years, metastatic cutaneous melanoma or melanoma with high risk of metastasis, the presence of BRAF V600 mutation, and treatment with BRAF inhibitors or a combination of BRAF and MEK inhibitors. The majority of patients developed skin toxicity during treatment. The most common cutaneous side effects were localized hyperkeratosis and verrucous keratosis. Other cutaneous side effects observed were photosensitivity, squamous cell carcinoma, and keratoacanthoma. Our results indicate that cutaneous side effects are generally observed during BRAF inhibitor monotherapy and are significantly different from those observed in patients treated with combination therapy.

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Imidazoles; Indoles; MAP Kinase Kinase Kinases; Melanoma; Melanoma, Cutaneous Malignant; Mutation; Oximes; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Diseases; Skin Neoplasms; Sulfonamides; Vemurafenib

2017
Rapid regression of metastatic brain tumours in a melanoma patient after dabrafenib/trametinib therapy.
    European journal of dermatology : EJD, 2017, 10-01, Volume: 27, Issue:5

    Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Imidazoles; Male; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Remission Induction; Skin Neoplasms

2017
MEK inhibitor trametinib does not prevent the growth of anaplastic lymphoma kinase (ALK)-addicted neuroblastomas.
    Science signaling, 2017, Nov-28, Volume: 10, Issue:507

    Activation of the RAS-RAF-MEK-ERK signaling pathway is implicated in driving the initiation and progression of multiple cancers. Several inhibitors targeting the RAS-MAPK pathway are clinically approved as single- or polyagent therapies for patients with specific types of cancer. One example is the MEK inhibitor trametinib, which is included as a rational polytherapy strategy for treating EML4-ALK-positive, EGFR-activated, or KRAS-mutant lung cancers and neuroblastomas that also contain activating mutations in the RAS-MAPK pathway. In addition, in neuroblastoma, a heterogeneous disease, relapse cases display an increased rate of mutations in

    Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Cell Line, Tumor; Female; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 7; Neuroblastoma; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Receptor Protein-Tyrosine Kinases; Xenograft Model Antitumor Assays

2017
Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence.
    Cell reports, 2017, Dec-05, Volume: 21, Issue:10

    Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution.

    Topics: Antineoplastic Agents, Hormonal; Benzimidazoles; Cell Line, Tumor; Estradiol; Evolution, Molecular; Female; Fulvestrant; Humans; Imidazoles; Indoles; Male; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-myc; Pyridones; Pyrimidinones; Quinolines; Signal Transduction; Sulfonamides

2017
Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE-compliant retrospective observational postauthorization study.
    Medicine, 2017, Volume: 96, Issue:52

    The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8-45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Compassionate Use Trials; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Oximes; Pyridones; Pyrimidinones; Retrospective Studies; Spain; Survival Analysis

2017
Acute encephalopathy with combination dabrafenib/trametinib therapy.
    Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 2017, Volume: 23, Issue:4

    Biomarkers have improved the clinical application of numerous targeted agents used to treat solid tumors. In melanoma, the finding that approximately 60% of tumor cells harbor specific Val600 mutations of BRAF has increased the likelihood of response to certain agents aimed at inhibiting the mutant kinase. While dabrafenib is an effective anti-tumor agent with acceptable tolerability in patients with BRAF-mutated melanoma, we report the development (and outcome) of a previously unpublished acute toxic reaction observed in a patient receiving the drug.

    Topics: Acute Disease; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Female; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2017
Development of Cutaneous Toxicities During Selective Anti-BRAF Therapies: Preventive Role of Combination with MEK Inhibitors.
    Acta dermato-venereologica, 2017, 02-08, Volume: 97, Issue:2

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Drug Eruptions; Female; Humans; Imidazoles; Indoles; Keratoacanthoma; Keratoderma, Palmoplantar; Keratosis, Actinic; Keratosis, Seborrheic; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Photosensitivity Disorders; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

2017
Targeting melanoma with front-line therapy does not abrogate Nodal-expressing tumor cells.
    Laboratory investigation; a journal of technical methods and pathology, 2017, Volume: 97, Issue:2

    Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. It is the leading cause of skin cancer deaths with a median overall survival for advanced-stage metastatic disease of <6 months. Despite advances in the field with conventional and targeted therapies, the heterogeneity of melanoma poses the greatest ongoing challenge, ultimately leading to relapse and progression to a more drug-resistant tumor in most patients. Particularly noteworthy are recent findings, indicating that these therapies exert selective pressure on tumors resulting in the activation of pathways associated with cancer stem cells that are unresponsive to current therapy. Our previous studies have shown how Nodal, an embryonic morphogen of the transforming growth factor-beta superfamily, is one of these critical factors that is reactivated in aggressive melanoma and resistant to conventional chemotherapy, such as dacarbazine. In the current study, we sought to determine whether BRAF inhibitor (BRAFi) therapy targeted Nodal-expressing tumor cells in uniquely matched unresectable stage III and IV melanoma patient samples before and after therapy that preceded their eventual death due to disease. The results demonstrate that BRAFi treatment failed to affect Nodal levels in melanoma tissues. Accompanying experiments in soft agar and in nude mice showed the advantage of using combinatorial treatment with BRAFi plus anti-Nodal monoclonal antibody to suppress tumor growth and metastasis. These data provide a promising new approach using front-line therapy combined with targeting a cancer stem cell-associated molecule-producing a more efficacious response than monotherapy.

    Topics: Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Cell Line, Tumor; Female; Humans; Imidazoles; Immunohistochemistry; Lung Neoplasms; Melanoma; Mice, Nude; Molecular Targeted Therapy; Mutation; Nodal Protein; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

2017
Erythema Nodosum-Like Panniculitis as a False-Positive 18F-FDG PET/CT in Advanced Melanoma Treated With Dabrafenib and Trametinib.
    Clinical nuclear medicine, 2017, Volume: 42, Issue:1

    We present a 35-year-old woman with left axillary mass. Histopathological analysis revealed metastatic infiltration for BRAF-mutant melanoma. F-FDG PET/CT showed bilateral axillary lymphadenopathy as well as bone and subcutaneous metastases. Dabrafenib (a BRAF inhibitor) and trametinib (a MEK inhibitor) combined therapy was started with a complete metabolic response established by 2 consecutive PET/CT scans. A follow-up PET/CT showed FDG uptake in several subcutaneous nodules in both distal legs, suggesting metastases. Painless cutaneous lesions were observed on physical examination, and biopsy revealed erythema nodosum-like panniculitis.

    Topics: Adult; Antineoplastic Agents; Erythema Nodosum; False Positive Reactions; Female; Fluorodeoxyglucose F18; Humans; Imidazoles; Melanoma; Oximes; Panniculitis; Positron Emission Tomography Computed Tomography; Pyridones; Pyrimidinones; Radiopharmaceuticals

2017
A Transcriptional Signature Identifies LKB1 Functional Status as a Novel Determinant of MEK Sensitivity in Lung Adenocarcinoma.
    Cancer research, 2017, 01-01, Volume: 77, Issue:1

    LKB1 is a commonly mutated tumor suppressor in non-small cell lung cancer that exerts complex effects on signal transduction and transcriptional regulation. To better understand the downstream impact of loss of functional LKB1, we developed a transcriptional fingerprint assay representing this phenotype. This assay was predictive of LKB1 functional loss in cell lines and clinical specimens, even those without detected sequence alterations in the gene. In silico screening of drug sensitivity data identified putative LKB1-selective drug candidates, revealing novel associations not apparent from analysis of LKB1 mutations alone. Among the candidates, MEK inhibitors showed robust association with signature expression in both training and testing datasets independent of RAS/RAF mutations. This susceptibility phenotype is directly altered by RNA interference-mediated LKB1 knockdown or by LKB1 re-expression into mutant cell lines and is readily observed in vivo using a xenograft model. MEK sensitivity is dependent on LKB1-induced changes in AKT and FOXO3 activation, consistent with genomic and proteomic analyses of LKB1-deficient lung adenocarcinomas. Our findings implicate the MEK pathway as a potential therapeutic target for LKB1-deficient cancers and define a practical NanoString biomarker to identify functional LKB1 loss. Cancer Res; 77(1); 153-63. ©2016 AACR.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; AMP-Activated Protein Kinase Kinases; Animals; Benzimidazoles; Biomarkers, Tumor; Drug Resistance, Neoplasm; Female; Heterografts; Humans; Immunoblotting; Lung Neoplasms; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Mice, SCID; Oligonucleotide Array Sequence Analysis; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyridones; Pyrimidinones; Transcriptome

2017
Pharmacokinetics of dabrafenib in a patient with metastatic melanoma undergoing haemodialysis.
    Pigment cell & melanoma research, 2017, Volume: 30, Issue:1

    The combination of dabrafenib and trametinib is a standard of care for the management of BRAF mutant metastatic melanoma. Clinical trials excluded patients with end-stage kidney disease (ESKD), and as such, no data are available regarding the safety, efficacy and pharmacokinetics of these drugs in such patients. Here, we present the case of a 78-yr-old male patient with ESKD managed with haemodialysis (HD), treated with dabrafenib and trametinib at reduced doses. The patient has had a partial response, and this response continues at 9 months since our last follow-up without any dose escalation. Treatment was complicated by the development of diarrhoea, attributed to trametinib, necessitating temporary cessation of trametinib. Pharmacokinetic profiling of dabrafenib was undertaken, and its metabolites were similar pre- and post-dialysis and comparable to those in patients with normal renal function. Moreover, HD did not lower the plasma concentration of dabrafenib or trametinib. It is feasible to administer dabrafenib, in combination with trametinib, to patients with ESKD undergoing HD.

    Topics: Aged; Antineoplastic Agents; Humans; Imidazoles; Kidney Failure, Chronic; Male; Melanoma; Oximes; Pyridones; Pyrimidinones; Renal Dialysis; Tissue Distribution; Treatment Outcome

2017
Trametinib plus 4-Methylumbelliferone Exhibits Antitumor Effects by ERK Blockade and CD44 Downregulation and Affects PD-1 and PD-L1 in Malignant Pleural Mesothelioma.
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2017, Volume: 12, Issue:3

    Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy in which the mitogen-activated protein kinase pathway plays a critical role in the regulation of tumorigenesis. Hyaluronic acid (HA) is a major component of the extracellular matrix, and elevated HA levels with a concurrent increase in malignant properties are associated with MPM.. We evaluated the effects of trametinib, a mitogen-activated protein kinase (MEK) inhibitor, and 4-methylumbelliferone (4-MU), an HA synthesis inhibitor, alone and in combination on MPM cells in vitro and in vivo. We studied the effects of trametinib, 4-MU, and their combination on MPM cells by using cell viability assays, Western blot analysis, and a mouse xenograft model.. Trametinib and 4-MU exhibited antiproliferative activity in MPM cells. Trametinib blocked MEK-dependent extracellular signal-regulated kinase (ERK) phosphorylation and decreased CD44 expression in a concentration-dependent manner. Trametinib inhibited the expression of Fra-1 (the activator protein 1 [AP1] component), inhibited ERK phosphorylation, and decreased CD44 expression. 4-MU inhibited ERK phosphorylation but not CD44 expression. In a mouse xenograft model, trametinib and 4-MU alone suppressed tumor growth compared with a control. The combination had a greater inhibitory effect than either monotherapy. Immunohistochemical analysis showed that trametinib treatment alone significantly reduced expression of programmed cell death 1 ligand 1. Furthermore, the combination of trametinib and 4-MU resulted in higher expression of programmed cell death 1 and programmed cell death 1 ligand 1 than did the 4-MU treatment alone.. Our results suggest that trametinib and 4-MU are promising therapeutic agents in MPM and that further study of the combination is warranted.

    Topics: Animals; Antineoplastic Agents; Apoptosis; B7-H1 Antigen; Cell Proliferation; Drug Therapy, Combination; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation, Neoplastic; Humans; Hyaluronan Receptors; Hymecromone; Indicators and Reagents; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Mice, Inbred BALB C; Mice, Nude; Pleural Neoplasms; Programmed Cell Death 1 Receptor; Pyridones; Pyrimidinones; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2017
Trametinib after disease reactivation under dabrafenib in Erdheim-Chester disease with both
    Blood, 2017, 02-16, Volume: 129, Issue:7

    Topics: Drug Resistance; Erdheim-Chester Disease; Female; Humans; Imidazoles; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Oximes; Point Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones

2017
Genome-Wide CRISPR Screen Identifies Regulators of Mitogen-Activated Protein Kinase as Suppressors of Liver Tumors in Mice.
    Gastroenterology, 2017, Volume: 152, Issue:5

    It has been a challenge to identify liver tumor suppressors or oncogenes due to the genetic heterogeneity of these tumors. We performed a genome-wide screen to identify suppressors of liver tumor formation in mice, using CRISPR-mediated genome editing.. We identified 4 candidate liver tumor suppressor genes not previously associated with liver cancer (Nf1, Plxnb1, Flrt2, and B9d1). CRISPR-mediated knockout of Nf1, a negative regulator of RAS, accelerated liver tumor formation in mice. Loss of Nf1 or activation of RAS up-regulated the liver progenitor cell markers HMGA2 and SOX9. RAS pathway inhibitors suppressed the activation of the Hmga2 and Sox9 genes that resulted from loss of Nf1 or oncogenic activation of RAS. Knockdown of HMGA2 delayed formation of xenograft tumors from cells that expressed oncogenic RAS. In human HCCs, low levels of NF1 messenger RNA or high levels of HMGA2 messenger RNA were associated with shorter patient survival time. Liver cancer cells with inactivation of Plxnb1, Flrt2, and B9d1 formed more tumors in mice and had increased levels of mitogen-activated protein kinase phosphorylation.. Using a CRISPR-based strategy, we identified Nf1, Plxnb1, Flrt2, and B9d1 as suppressors of liver tumor formation. We validated the observation that RAS signaling, via mitogen-activated protein kinase, contributes to formation of liver tumors in mice. We associated decreased levels of NF1 and increased levels of its downstream protein HMGA2 with survival times of patients with HCC. Strategies to inhibit or reduce HMGA2 might be developed to treat patients with liver cancer.

    Topics: Animals; Benzimidazoles; Blotting, Western; Butadienes; Carcinoma, Hepatocellular; Cell Line, Tumor; CRISPR-Cas Systems; Cytoskeletal Proteins; DNA, Neoplasm; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Genes, Neurofibromatosis 1; Genome-Wide Association Study; Hepatocytes; High-Throughput Nucleotide Sequencing; HMGA Proteins; HMGA2 Protein; Humans; Immunohistochemistry; Liver Neoplasms; Liver Neoplasms, Experimental; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Nude; Mitogen-Activated Protein Kinases; Nerve Tissue Proteins; Niacinamide; Nitriles; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Pyridones; Pyrimidinones; ras Proteins; Real-Time Polymerase Chain Reaction; Receptors, Cell Surface; Sequence Analysis, DNA; Sorafenib; Survival Analysis; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

2017
The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737.
    Molecular cancer therapeutics, 2017, Volume: 16, Issue:1

    Topics: Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Humans; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Morpholines; Multiprotein Complexes; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Piperazines; Protein Binding; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Pyridones; Pyrimidinones; Sulfonamides; TOR Serine-Threonine Kinases

2017
Cutaneous Reactions in Children Treated with the Mitogen-Activated Protein Kinase Extracellular Signal-Regulated Kinase Inhibitor Trametinib for Neural Tumors.
    Pediatric dermatology, 2017, Volume: 34, Issue:1

    The mitogen-activated protein kinase (MAPK) pathway is a target for the treatment of a growing number of malignancies. The cutaneous reactions to medications that inhibit this pathway have not been described in children.. A retrospective chart review was completed for eight children with neural tumors treated with the MAPK extracellular signal-regulated kinase inhibitor trametinib. All children were evaluated by a pediatric dermatologist with documentation of cutaneous findings.. All patients had at least two separate skin reactions while on treatment with trametinib. Common skin findings included xerotic dermatitis, bacterial folliculitis, acneiform eruptions, paronychia, and hair thinning. No child needed to discontinue use of trametinib due to cutaneous toxicities.. Cutaneous reactions are common in children receiving trametinib. Identification of these reactions is the initial step in establishing treatment guidelines that will minimize skin eruptions and subsequent interruption of trametinib treatment.

    Topics: Adolescent; Child; Child, Preschool; Exanthema; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Male; Neoplasms, Neuroepithelial; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Retrospective Studies

2017
Dual inhibition of the PI3K/AKT/mTOR pathway suppresses the growth of leiomyosarcomas but leads to ERK activation through mTORC2: biological and clinical implications.
    Oncotarget, 2017, Jan-31, Volume: 8, Issue:5

    The PI3K/AKT/mTOR pathway plays a crucial role in the development of leiomyosarcomas (LMSs). In this study, we tested the efficacy of dual PI3K/mTOR (BEZ235), PI3K (BKM120) and mTOR (everolimus) inhibitors in three human LMS cell lines. In vitro and in vivo studies using LMS cell lines showed that BEZ235 has a significantly higher anti-tumor effect than either BKM120 or everolimus, resulting in a greater reduction in tumor growth and more pronounced inhibitory effects on mitotic activity and PI3K/AKT/mTOR signaling. Strikingly, BEZ235 but neither BKM120 nor everolimus markedly enhanced the ERK pathway. This effect was reproduced by the combination of BKM120 and everolimus, suggesting the involvement of mTORC2 via a PI3K-independent mechanism. Silencing of RICTOR in LMS cells confirmed the role of mTORC2 in the regulation of ERK activity. Combined treatment with BEZ235 and GSK1120212, a potent MEK inhibitor, resulted in synergistic growth inhibition and apoptosis induction in vitro and in vivo. These findings document for the first time that dual PI3K/mTOR inhibition in leiomyosarcomas suppress a negative feedback loop mediated by mTORC2, leading to enhanced ERK pathway activity. Thus, combining a dual PI3K/mTOR inhibitor with MEK inhibitors may be a relevant approach to increase anti-tumor activity and prevent drug resistance in patients with LMS.

    Topics: Aminopyridines; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Activation; Everolimus; Extracellular Signal-Regulated MAP Kinases; Humans; Imidazoles; Leiomyosarcoma; MAP Kinase Kinase Kinases; Mechanistic Target of Rapamycin Complex 2; Mice; Morpholines; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Quinolines; Rapamycin-Insensitive Companion of mTOR Protein; RNA Interference; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Transfection; Tumor Burden; Xenograft Model Antitumor Assays

2017
Report of effective trametinib therapy in 2 children with progressive hypothalamic optic pathway pilocytic astrocytoma: documentation of volumetric response.
    Journal of neurosurgery. Pediatrics, 2017, Volume: 19, Issue:3

    Brain tumors are the most common solid tumor in childhood, and astrocytomas account for the largest proportion of these tumors. Increasing sophistication in genetic testing has allowed for the detection of specific mutations within tumor subtypes that may represent targets for individualized tumor treatment. The mitogen-activating protein kinase (MAPK) pathway and, more specifically, BRAF mutations have been shown to be prevalent in pediatric pilocytic astrocytomas and may represent one such area to target. Herein, the authors describe 2 cases of inoperable, chemotherapy-resistant pediatric pilocytic astrocytomas with a documented response to trametinib, an MAPK pathway inhibitor. While these cases were not treated in the setting of a clinical trial, their data support further ongoing clinical trial investigation to evaluate the safety and efficacy of this agent in pediatric low-grade gliomas.

    Topics: Antineoplastic Agents; Astrocytoma; Child, Preschool; Disease Progression; Female; Humans; Hypothalamic Neoplasms; Infant; Optic Nerve Neoplasms; Organ Size; Pyridones; Pyrimidinones; Treatment Outcome

2017
Durable Response to Combination of Dabrafenib and Trametinib in BRAF V600E-Mutated Non-small-cell Lung Cancer.
    Clinical lung cancer, 2017, Volume: 18, Issue:3

    Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; DNA Mutational Analysis; Female; Humans; Imidazoles; Lung Neoplasms; MAP Kinase Kinase Kinases; Middle Aged; Molecular Targeted Therapy; Mutation; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Remission Induction

2017
Enhanced MAPK signaling is essential for CSF3R-induced leukemia.
    Leukemia, 2017, Volume: 31, Issue:8

    Both membrane-proximal and truncation mutations in CSF3R have recently been reported to drive the onset of chronic neutrophilic leukemia (CNL). Here we show that although truncation mutation alone cannot induce leukemia, both proximal and compound mutations (proximal and truncation mutations on same allele) are leukemogenic with a disease latency of 90 and 23 days, respectively. Comparative whole-genome expression profiling and biochemical experiments revealed that induced expression of Mapk adaptor protein Ksr1 and enhanced Mapk signaling are crucial to leukemogenesis by CSF3R proximal and compound mutants. Moreover, inhibition of Mek1/2 by trametinib alone is sufficient to suppress leukemia induced by both CSF3R proximal and ruxolitinib-resistant compound mutations. Together, these findings elucidate a Mapk-dependent mechanism of CSF3R-induced pathogenesis, and they establish the rationale for clinical evaluation of MEK1/2 inhibition in CNL.

    Topics: Animals; Humans; Janus Kinase 2; Leukemia; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mutation; Pyridones; Pyrimidinones; Receptors, Colony-Stimulating Factor

2017
Indirect treatment comparison of dabrafenib plus trametinib versus vemurafenib plus cobimetinib in previously untreated metastatic melanoma patients.
    Journal of hematology & oncology, 2017, 01-04, Volume: 10, Issue:1

    Metastatic melanoma is an aggressive form of skin cancer with a high mortality rate and the fastest growing global incidence rate of all malignancies. The introduction of BRAF/MEK inhibitor combinations has yielded significant increases in PFS and OS for melanoma. However, at present, no direct comparisons between different BRAF/MEK combinations have been conducted. In light of this, an indirect treatment comparison was performed between two BRAF/MEK inhibitor combination therapies for metastatic melanoma, dabrafenib plus trametinib and vemurafenib plus cobimetinib, in order to understand the relative efficacy and toxicity profiles of these therapies.. A systematic literature search identified two randomized trials as suitable for indirect comparison: the coBRIM trial of vemurafenib plus cobimetinib versus vemurafenib and the COMBI-v trial of dabrafenib plus trametinib versus vemurafenib. The comparison followed the method of Bucher et al. and analyzed both efficacy (overall survival [OS], progression-free survival [PFS], and overall response rate [ORR]) and safety outcomes (adverse events [AEs]).. The indirect comparison revealed similar efficacy outcomes between both therapies, with no statistically significant difference between therapies for OS (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.68 - 1.30), PFS (HR 1.05, 95% CI 0.79 - 1.40), or ORR (risk ratio [RR] 0.90, 95% CI 0.74 - 1.10). Dabrafenib plus trametinib differed significantly from vemurafenib plus cobimetinib with regard to the incidence of treatment-related AE (RR 0.92, 95% CI 0.87 - 0.97), any AE grade ≥3 (RR 0.71, 95% CI 0.60 - 0.85) or dose interruption/modification (RR 0.77, 95% CI 0.60 - 0.99). Several categories of AEs occurred significantly more frequently with vemurafenib plus cobimetinib, while some occurred significantly more frequently with dabrafenib plus trametinib. For severe AEs (grade 3 or above), four occurred significantly more frequently with vemurafenib plus cobimetinib and no severe AE occurred significantly more frequently with dabrafenib plus trametinib.. This indirect treatment comparison suggested that dabrafenib plus trametinib had comparable efficacy to vemurafenib plus cobimetinib but was associated with reduced adverse events.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Oximes; Piperidines; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome; Vemurafenib; Young Adult

2017
Dabrafenib Effective in Pediatric Glioma.
    Cancer discovery, 2017, Volume: 7, Issue:1

    A phase I/II clinical trial suggests that dabrafenib shrinks or stabilizes low-grade gliomas in children with the BRAF V600E mutation. Objective, durable responses occurred in 38% of patients, and the side effects were less severe than with chemotherapy. The researchers have started a second trial for patients with glioma and other BRAF-mutant tumor types, this time evaluating dabrafenib combined with trametinib.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Clinical Trials as Topic; Disease-Free Survival; Female; Glioma; Humans; Imidazoles; Male; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Survival Analysis; Treatment Outcome

2017
Tumor-Targeting Salmonella typhimurium A1-R Sensitizes Melanoma With a BRAF-V600E Mutation to Vemurafenib in a Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model.
    Journal of cellular biochemistry, 2017, Volume: 118, Issue:8

    Previously, a BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. Trametinib (TRA), an MEK inhibitor, caused tumor regression. In contrast, another MEK inhibitor, cobimetinib (COB) could slow but not arrest growth or cause regression of the melanoma PDOX. First-line therapy temozolomide (TEM) could slow but not arrest tumor growth or cause regression. In addition, vemurafenib (VEM) was not effective even though VEM is supposed to target the BRAF-V600E mutation. We also previously demonstrated that tumor-targeting with S. typhimurium A1-R combined with TEM was significantly more effective than either S. typhimurium A1-R alone or TEM alone on the melanoma PDOX with the BRAF-V600E mutation. The present study used this PDOX model of melanoma to test its sensitivity to VEM combined with S. typhimurium A1-R compared to VEM alone and VEM combined with COB. VEM combined with S. typhimurium A1-R was significantly more effective than VEM alone or VEM combined with COB (P = 0.0216) which is currently first line therapy for advanced melanoma with a BRAF-V600E mutation. J. Cell. Biochem. 118: 2314-2319, 2017. © 2017 Wiley Periodicals, Inc.

    Topics: Aged; Animals; Azetidines; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Indoles; Melanoma; Mice; Mice, Nude; Microscopy, Confocal; Microscopy, Electron, Transmission; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Salmonella typhimurium; Sulfonamides; Vemurafenib; Xenograft Model Antitumor Assays

2017
The purpose of repurposing.
    Oncotarget, 2017, 02-21, Volume: 8, Issue:8

    Topics: Anthelmintics; Humans; Mebendazole; Melanoma; Pyridones; Pyrimidinones

2017
Combined blockade of Tim-3 and MEK inhibitor enhances the efficacy against melanoma.
    Biochemical and biophysical research communications, 2017, 03-04, Volume: 484, Issue:2

    Insights into the role of the mitogen-activated protein kinase (MAPK) pathway and immune checkpoints have led combined targeted therapy and immunotherapy to be a promising regimen. Trametinib, as a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, has demonstrated effectiveness in patients with advanced melanoma. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3), an immune checkpoint molecule, participates in multiple negative regulation of antitumor immunity. We for the first time to our knowledge reported the combination of trametinib and anti-Tim-3 monoclonal antibody (mAb) in treating B16-F10 melanoma mice. We discovered that trametinib remarkably promoted apoptosis and inhibited cell proliferation while inhibition of MEK improved the expression of Tim-3 and caused the decrease of CD8

    Topics: Animals; Antineoplastic Agents; Hepatitis A Virus Cellular Receptor 2; MAP Kinase Kinase Kinases; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Pyridones; Pyrimidinones; Up-Regulation

2017
Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma.
    Molecular cancer therapeutics, 2017, Volume: 16, Issue:3

    Patients with metastatic uveal melanoma usually die within 1 year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to MEK inhibitors in metastatic uveal melanoma. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and Bmf, contributes to HGF-mediated resistance to MEK inhibitors. Targeting HGF/cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor, overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. We further determined that activation of PI3Kα/γ/δ isoforms mediates the resistance to MEK inhibitors by HGF. Combination of LY2801653 with trametinib decreases AKT phosphorylation and promotes proapoptotic PARP cleavage in metastatic uveal melanoma explants. Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic uveal melanoma may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in the liver.

    Topics: Adaptor Proteins, Signal Transducing; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Drug Resistance, Neoplasm; GTP-Binding Protein alpha Subunits, Gq-G11; Hepatic Stellate Cells; Hepatocyte Growth Factor; Humans; JNK Mitogen-Activated Protein Kinases; Melanoma; Mitogen-Activated Protein Kinase Kinases; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridones; Pyrimidinones; Signal Transduction; Uveal Neoplasms

2017
The HDAC inhibitor AR42 interacts with pazopanib to kill trametinib/dabrafenib-resistant melanoma cells in vitro and in vivo.
    Oncotarget, 2017, Mar-07, Volume: 8, Issue:10

    Studies focused on the killing of activated B-RAF melanoma cells by the histone deacetylase (HDAC) inhibitor AR42. Compared to other tumor cell lines, PDX melanoma isolates were significantly more sensitive to AR42-induced killing. AR42 and the multi-kinase inhibitor pazopanib interacted to activate: an eIF2α-Beclin1 pathway causing autophagosome formation; an eIF2α-DR4/DR5/CD95 pathway; and an eIF2α-dependent reduction in the expression of c-FLIP-s, MCL-1 and BCL-XL. AR42 did not alter basal chaperone activity but increased the ability of pazopanib to inhibit HSP90, HSP70 and GRP78. AR42 and pazopanib caused HSP90/HSP70 dissociation from RAF-1 and B-RAF that resulted in reduced 'RAF' expression. The drug combination activated a DNA-damage-ATM-AMPK pathway that was associated with: NFκB activation; reduced mTOR S2448 and ULK-1 S757 phosphorylation; and increased ULK-1 S317 and ATG13 S318 phosphorylation. Knock down of PERK, eIF2α, Beclin1, ATG5 or AMPKα, or expression of IκB S32A S36A, ca-mTOR or TRX, reduced cell killing. AR42, via lysosomal degradation, reduced the protein expression of HDACs 2/5/6/10/11. In vivo, a 3-day exposure of dabrafenib/trametinib resistant melanoma cells to the AR42 pazopanib combination reduced tumor growth and enhanced survival from ~25 to ~40 days. Tumor cells that had adapted through therapy exhibited elevated HGF expression and the c-MET inhibitor crizotinib enhanced AR42 pazopanib lethality in this evolved drug-resistant population.

    Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Autophagosomes; Blotting, Western; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Endoplasmic Reticulum Chaperone BiP; Eukaryotic Initiation Factor-2; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Imidazoles; Indazoles; Kaplan-Meier Estimate; Male; Melanoma; Mice, Nude; Microscopy, Fluorescence; Oximes; Phenylbutyrates; Pyridones; Pyrimidines; Pyrimidinones; RNA Interference; Signal Transduction; Sulfonamides; Xenograft Model Antitumor Assays

2017
The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma.
    Oncotarget, 2017, Feb-21, Volume: 8, Issue:8

    Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes. Downstream ERK targets for cell cycle, including cMYC, were down-regulated, consistent with S- phase suppression by MBZ+trametinib, while apoptosis markers, including cleaved caspase-3, cleaved PARP and a sub-G1 population, were all increased with time. These data suggest that MBZ, a well-tolerated off-patent approved drug, should be considered as a therapeutic option in combination with trametinib, for patients with NRASQ61mut or other non-V600E BRAF mutant melanomas.

    Topics: Animals; Antinematodal Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; GTP Phosphohydrolases; Humans; Immunoblotting; Mebendazole; Melanoma; Membrane Proteins; Mice; Protein Array Analysis; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2017
ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition.
    Cell reports, 2017, 02-07, Volume: 18, Issue:6

    Intrinsic resistance and RTK-RAS-MAPK pathway reactivation has limited the effectiveness of MEK and RAF inhibitors (MAPKi) in RAS- and RAF-mutant cancers. To identify genes that modulate sensitivity to MAPKi, we performed genome-scale CRISPR-Cas9 loss-of-function screens in two KRAS mutant pancreatic cancer cell lines treated with the MEK1/2 inhibitor trametinib. Loss of CIC, a transcriptional repressor of ETV1, ETV4, and ETV5, promoted survival in the setting of MAPKi in cancer cells derived from several lineages. ATXN1L deletion, which reduces CIC protein, or ectopic expression of ETV1, ETV4, or ETV5 also modulated sensitivity to trametinib. ATXN1L expression inversely correlates with response to MAPKi inhibition in clinical studies. These observations identify the ATXN1L-CIC-ETS transcription factor axis as a mediator of resistance to MAPKi.

    Topics: Animals; Antigens, Protozoan; Cell Line, Tumor; Drug Resistance, Neoplasm; HCT116 Cells; Humans; MAP Kinase Signaling System; Mice; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; raf Kinases; Repressor Proteins; Transcription Factors

2017
Real-time genomic profiling of histiocytoses identifies early-kinase domain BRAF alterations while improving treatment outcomes.
    JCI insight, 2017, 02-09, Volume: 2, Issue:3

    Many patients with histiocytic disorders such as Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) have treatment-refractory disease or suffer recurrences. Recent findings of gene mutations in histiocytoses have generated options for targeted therapies. We sought to determine the utility of prospective sequencing of select genes to further characterize mutations and identify targeted therapies for patients with histiocytoses. Biopsies of 72 patients with a variety of histiocytoses underwent comprehensive genomic profiling with targeted DNA and RNA sequencing. Fifteen patients (21%) carried the known

    Topics: 3T3 Cells; Adult; Anaplastic Lymphoma Kinase; Animals; Drug Resistance, Neoplasm; Female; Histiocytosis; Humans; Imidazoles; Infant; Male; MAP Kinase Kinase 1; Mice; Mutation; Oximes; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sequence Analysis, DNA; Sequence Analysis, RNA; Treatment Outcome; Young Adult

2017
PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer.
    Scientific reports, 2017, 02-21, Volume: 7

    Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies.

    Topics: Animals; Cell Line, Tumor; Drug Synergism; Everolimus; Female; Humans; Janus Kinase 1; MAP Kinase Kinase Kinases; Mice; Mice, Nude; Neoplastic Stem Cells; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Pyridones; Pyrimidinones; RNA Interference; RNA, Small Interfering; STAT3 Transcription Factor; TOR Serine-Threonine Kinases

2017
Recurrent tattoo reactions in a patient treated with BRAF and MEK inhibitors.
    Journal of the European Academy of Dermatology and Venereology : JEADV, 2017, Volume: 31, Issue:8

    Topics: Adult; Antineoplastic Agents; Dermatitis, Allergic Contact; Female; Humans; Imidazoles; MAP Kinase Kinase 1; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Recurrence; Tattooing

2017
BRAF Signaling Pathway Inhibition, Podocyte Injury, and Nephrotic Syndrome.
    American journal of kidney diseases : the official journal of the National Kidney Foundation, 2017, Volume: 70, Issue:1

    Dabrafenib and trametinib, BRAF and MEK inhibitors, respectively, are effective targeted metastatic melanoma therapies, but little is known about their nephrotoxicity. Although tubulointerstitial injury has been the most widely reported renal side effect of targeted melanoma therapy, nephrotic syndrome has not been reported before. We report on a patient with metastatic melanoma who developed nephrotic syndrome during dabrafenib and trametinib treatment. Kidney biopsy showed diffuse loss of podocyte cytoarchitecture, extensive foot-process effacement, and glomerular endothelial injury. Kidney function and glomerular ultrastructural changes recovered fully after drug withdrawal. In vitro, BRAF inhibition decreased PLCε1 expression in podocytes, accompanied by a reduction in nephrin expression and an increase in permeability to albumin. Additionally, these drugs inhibited the podocyte-vascular endothelial growth factor (VEGF) system. In addition to implications for nephrotic syndrome pathophysiology, we suggest that patients given dabrafenib and trametinib be monitored closely for potential glomerular damage.

    Topics: Aged; Antineoplastic Agents; Female; Humans; Imidazoles; Melanoma; Nephrotic Syndrome; Oximes; Podocytes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Signal Transduction; Skin Neoplasms

2017
Dabrafenib plus trametinib rechallenge in four melanoma patients who previously progressed on this combination.
    Melanoma research, 2017, Volume: 27, Issue:2

    In unresectable or metastatic melanoma with a BRAF V600 mutation, combined BRAF/MEK targeted therapy improves clinical outcomes. Yet, disease progression because of acquired resistance occurs in the majority of patients. There is emerging evidence that resistance to BRAF-inhibitor-based targeted therapy can be reversible in some cases. We retrospectively analyzed four patients with BRAF-mutant stage IV cutaneous melanoma who were treated with dabrafenib plus trametinib and rechallenged with the same combination after previously experiencing progression. At initial treatment with dabrafenib plus trametinib, three patients achieved a partial response and one patient achieved a complete response. Progression-free survival varied from 9.9 to 24.3 (median 19.8) months. The targeted therapy-free interval ranged from 2.3 to 11.7 (median 8.8) months. At rechallenge, all four patients had a partial response, with progression-free survival ranging from 3.6 to 6.8 (median 5.2) months. Clinical benefit and a second radiological response can be obtained upon readministration of dabrafenib plus trametinib after previously acquiring resistance to this combination. A better understanding of the biological underpinnings of genomic and nongenomic mechanisms of resistance to BRAF-inhibitor-based targeted therapy is needed to identify patients who may benefit from this rechallenge approach.

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Disease-Free Survival; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Response Evaluation Criteria in Solid Tumors; Retreatment; Retrospective Studies; Skin Neoplasms

2017
MEK inhibition appears to improve symptom control in primary NRAS-driven CNS melanoma in children.
    British journal of cancer, 2017, Apr-11, Volume: 116, Issue:8

    Primary melanoma of the CNS in children is extremely rare, and usually linked to congenital melanocytic naevus syndrome, caused by mosaicism for oncogenic NRAS mutations. Outcome is fatal in all cases. Data from murine and in vitro studies suggest that MEK inhibition is a possible therapeutic option.. Four children with NRAS-mutated CNS melanoma were treated with Trametinib on a compassionate basis.. All four had an improvement in symptoms and objectively in signs. These varied from mild improvement for 1 month, to a sustained symptom-free period of 9 months in one case. In all cases there was eventual disease progression through treatment, followed by rapid death after discontinuation. There were no clinically-significant side effects.. Trametinib is the first therapy to show any objective or measurable effect in NRAS-mutated primary CNS melanoma, with few side effects in this small series. The role of this therapy should be explored further in this rare paediatric tumour.

    Topics: Central Nervous System Neoplasms; Child, Preschool; Female; GTP Phosphohydrolases; Humans; Infant; Male; MAP Kinase Kinase 1; Melanoma; Membrane Proteins; Mutation; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

2017
Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAF
    The Lancet. Oncology, 2017, Volume: 18, Issue:4

    Patients with BRAF. In this open-label, single arm, dual-centre, phase 2 academic study in Belgium, patients aged 18 years or older with BRAF. Between April 5, 2014, and Feb 2, 2016, 25 patients were enrolled and initiated treatment in our study. A partial response was documented in eight (32%) of 25 patients (95% CI 15-54; six patients had progressed on previous treatment with dabrafenib plus trametinib and two patients had progressed on previous BRAF inhibitor monotherapy). Stable disease was noted in ten patients (40%; 95% CI 21-61). Rechallenge with dabrafenib plus trametinib was well tolerated. There were no unexpected or grade 4 or 5 treatment-related adverse events. Grade 3 adverse events occurred in two patients (8%; panniculitis [n=1] and pyrexia [n=1]). Serious adverse events which occurred on study were one patient with an Addison crisis triggered by grade 2 pyrexia symptoms that resolved after discontinuation of dabrafenib and trametinib. No patients died as a result of study treatment.. Rechallenge with dabrafenib plus trametinib showed anti-tumour activity in patients who had previously progressed on BRAF inhibitors and as such, rechallenge represents a potential new treatment option for these patients.. Vlaamse Liga Tegen Kanker, Novartis.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Follow-Up Studies; Humans; Imidazoles; Lymphatic Metastasis; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Neoplasm Staging; Oximes; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Survival Rate

2017
Arrhythmias in a patient with metastatic melanoma treated with targeted therapy and implantable cardioverter defibrillator.
    The British journal of dermatology, 2017, Volume: 177, Issue:2

    Topics: Adult; Antineoplastic Agents; Arrhythmias, Cardiac; Defibrillators, Implantable; Heart Neoplasms; Humans; Imidazoles; Male; Melanoma; Molecular Targeted Therapy; Oximes; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

2017
Effective treatment with Dabrafenib and Trametinib for a BRAF-mutated metastatic dedifferentiated malignant spindle cell neoplasm.
    Journal of the European Academy of Dermatology and Venereology : JEADV, 2016, Volume: 30, Issue:7

    Topics: Aged; Antineoplastic Agents; Female; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Pyridones; Pyrimidinones

2016
Inhibiting MEK in MAPK pathway-activated myeloma.
    Leukemia, 2016, Volume: 30, Issue:4

    Topics: Biomarkers, Tumor; Cyclin D2; Follow-Up Studies; High-Throughput Nucleotide Sequencing; Humans; Integrin beta Chains; Male; MAP Kinase Kinase 1; MAP Kinase Signaling System; Middle Aged; Multiple Myeloma; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Receptors, CCR1; Retrospective Studies

2016
The distribution of BRAF gene fusions in solid tumors and response to targeted therapy.
    International journal of cancer, 2016, Feb-15, Volume: 138, Issue:4

    Although the BRAF V600E base substitution is an approved target for the BRAF inhibitors in melanoma, BRAF gene fusions have not been investigated as anticancer drug targets. In our study, a wide variety of tumors underwent comprehensive genomic profiling for hundreds of known cancer genes using the FoundationOne™ or FoundationOne Heme™ comprehensive genomic profiling assays. BRAF fusions involving the intact in-frame BRAF kinase domain were observed in 55 (0.3%) of 20,573 tumors, across 12 distinct tumor types, including 20 novel BRAF fusions. These comprised 29 unique 5' fusion partners, of which 31% (9) were known and 69% (20) were novel. BRAF fusions included 3% (14/531) of melanomas; 2% (15/701) of gliomas; 1.0% (3/294) of thyroid cancers; 0.3% (3/1,062) pancreatic carcinomas; 0.2% (8/4,013) nonsmall-cell lung cancers and 0.2% (4/2,154) of colorectal cancers, and were enriched in pilocytic (30%) vs. nonpilocytic gliomas (1%; p < 0.0001), Spitzoid (75%) vs. nonSpitzoid melanomas (1%; p = 0.0001), acinar (67%) vs. nonacinar pancreatic cancers (<1%; p < 0.0001) and papillary (3%) vs. nonpapillary thyroid cancers (0%; p < 0.03). Clinical responses to trametinib and sorafenib are presented. In conclusion, BRAF fusions are rare driver alterations in a wide variety of malignant neoplasms, but enriched in Spitzoid melanoma, pilocytic astrocytomas, pancreatic acinar and papillary thyroid cancers.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Child; Child, Preschool; Female; Gene Expression Profiling; Humans; Infant; Male; Middle Aged; Molecular Targeted Therapy; Neoplasms; Niacinamide; Oncogene Proteins, Fusion; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sorafenib; Transcriptome; Treatment Outcome; Young Adult

2016
Vemurafenib-induced toxic epidermal necrolysis: possible cross-reactivity with other sulfonamide compounds.
    The British journal of dermatology, 2016, Volume: 174, Issue:3

    Vemurafenib is a newly licensed target-directed medication. It has been proven to improve the survival of patients with metastatic melanoma and the BRAF(V600E) mutation; however, adverse cutaneous reactions are frequent. Few cases of life-threatening severe cutaneous adverse reactions (SCARs) induced by vemurafenib have been reported. Dabrafenib, another selective BRAF inhibitor, has been licensed recently as an alternative drug with the same indications. From a molecular point of view, both vemurafenib and dabrafenib contain a sulfonamide group; cross-reactivity to sulfonamide compounds has been reported in allergic patients. We report on a patient with vemurafenib-induced toxic epidermal necrolysis (TEN). In vitro analysis of lymphocyte reactivity to vemurafenib showed positive results, confirming drug causality. In addition, lymphocytes from the patient reacted to dabrafenib and to the antibiotic sulfonamide drug sulfamethoxazole. Moreover, lymphocytes from two patients with cutaneous adverse reactions to sulfamethoxazole also reacted to vemurafenib and dabrafenib in vitro. These data strongly suggest that there might be clinical cross-reactivity between BRAF inhibitors and sulfonamides in some patients. Thus, precautions should be taken to avoid sulfonamide drugs as much as possible in patients showing serious hypersensitivity reactions to vemurafenib and vice versa.

    Topics: Aged; Antineoplastic Agents; Drug Interactions; Drug Therapy, Combination; Humans; Imidazoles; Indoles; Male; Melanoma; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Stevens-Johnson Syndrome; Sulfonamides; Vemurafenib

2016
Preclinical Evidence That Trametinib Enhances the Response to Antiangiogenic Tyrosine Kinase Inhibitors in Renal Cell Carcinoma.
    Molecular cancer therapeutics, 2016, Volume: 15, Issue:1

    Sunitinib and pazopanib are antiangiogenic tyrosine kinase inhibitors (TKI) used to treat metastatic renal cell carcinoma (RCC). However, the ability of these drugs to extend progression-free and overall survival in this patient population is limited by drug resistance. It is possible that treatment outcomes in RCC patients could be improved by rationally combining TKIs with other agents. Here, we address whether inhibition of the Ras-Raf-MEK-ERK1/2 pathway is a rational means to improve the response to TKIs in RCC. Using a xenograft model of RCC, we found that tumors that are resistant to sunitinib have a significantly increased angiogenic response compared with tumors that are sensitive to sunitinib in vivo. We also observed significantly increased levels of phosphorylated ERK1/2 in the vasculature of resistant tumors, when compared with sensitive tumors. These data suggested that the Ras-Raf-MEK-ERK1/2 pathway, an important driver of angiogenesis in endothelial cells, remains active in the vasculature of TKI-resistant tumors. Using an in vitro angiogenesis assay, we identified that the MEK inhibitor (MEKI) trametinib has potent antiangiogenic activity. We then show that, when trametinib is combined with a TKI in vivo, more effective suppression of tumor growth and tumor angiogenesis is achieved than when either drug is utilized alone. In conclusion, we provide preclinical evidence that combining a TKI, such as sunitinib or pazopanib, with a MEKI, such as trametinib, is a rational and efficacious treatment regimen for RCC.

    Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Renal Cell; Cell Line, Tumor; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Drug Synergism; Endothelial Cells; Female; Humans; Indoles; Kidney Neoplasms; MAP Kinase Signaling System; Neovascularization, Pathologic; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Pyrroles; Sunitinib; Von Hippel-Lindau Tumor Suppressor Protein; Xenograft Model Antitumor Assays

2016
Dramatic Response of BRAF V600E Mutant Papillary Craniopharyngioma to Targeted Therapy.
    Journal of the National Cancer Institute, 2016, Volume: 108, Issue:2

    We recently reported that BRAF V600E is the principal oncogenic driver of papillary craniopharyngioma, a highly morbid intracranial tumor commonly refractory to treatment. Here, we describe our treatment of a man age 39 years with multiply recurrent BRAF V600E craniopharyngioma using dabrafenib (150mg, orally twice daily) and trametinib (2mg, orally twice daily). After 35 days of treatment, tumor volume was reduced by 85%. Mutations that commonly mediate resistance to MAPK pathway inhibition were not detected in a post-treatment sample by whole exome sequencing. A blood-based BRAF V600E assay detected circulating BRAF V600E in the patient's blood. Re-evaluation of the existing management paradigms for craniopharyngioma is warranted, as patient morbidity might be reduced by noninvasive mutation testing and neoadjuvant-targeted treatment.

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Craniopharyngioma; Craniotomy; Cytoreduction Surgical Procedures; Drug Administration Schedule; Glutamic Acid; Humans; Imidazoles; Magnetic Resonance Imaging; Male; Molecular Targeted Therapy; Mutation; Neoplasm Recurrence, Local; Neoplasm, Residual; Oximes; Pituitary Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome; Valine

2016
ERK Plays a Role in Chromosome Alignment and Participates in M-Phase Progression.
    Journal of cellular biochemistry, 2016, Volume: 117, Issue:6

    Cell division, a prerequisite for cell proliferation, is a process in which each daughter cell inherits one complete set of chromosomes. The mitotic spindle is a dedicated apparatus for the alignment and segregation of chromosomes. Extracellular signal-regulated kinase (ERK) 1/2 plays crucial roles in cell cycle progression, particularly during M-phase. Although, association with the mitotic spindle has been reported, the precise roles played by ERK in the dynamics of the mitotic spindle and in M-phase progression remain to be elucidated. In this study, we used MEK inhibitors U0126 and GSK1120212 to dissect the roles of ERK in M-phase progression and chromosome alignment. Fluorescence microscopy revealed that ERK is localized to the spindle microtubules in a manner independent of Src kinase, which is one of the kinases upstream of ERK at mitotic entry. ERK inhibition induces an increase in the number of prophase cells and a decrease in the number of anaphase cells. Time-lapse imaging revealed that ERK inhibition perturbs chromosome alignment, thereby preventing cells from entering anaphase. These results suggest that ERK plays a role in M-phase progression by regulating chromosome alignment and demonstrate one of the mechanisms by which the aberration of ERK signaling may produce cancer cells.

    Topics: Anaphase; Animals; Butadienes; Cell Line; Chromosomes, Human; Extracellular Signal-Regulated MAP Kinases; Humans; Nitriles; Prophase; Pyridones; Pyrimidinones; Spindle Apparatus; Swine; Time-Lapse Imaging

2016
Identification of an "Exceptional Responder" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted Therapy.
    Molecular cancer research : MCR, 2016, Volume: 14, Issue:2

    The identification of somatic genetic alterations that confer sensitivity to pharmacologic inhibitors has led to new cancer therapies. To identify mutations that confer an exceptional dependency, shRNA-based loss-of-function data were analyzed from a dataset of numerous cell lines to reveal genes that are essential in a small subset of cancer cell lines. Once these cell lines were determined, detailed genomic characterization from these cell lines was utilized to ascertain the genomic aberrations that led to this extreme dependency. This method, in a large subset of lung cancer cell lines, yielded a single lung adenocarcinoma cell line, NCI-H1437, which is sensitive to RNA interference of MAP2K1 expression. Notably, NCI-H1437 is the only lung cancer cell line included in the dataset with a known activating mutation in MAP2K1 (Q56P). Subsequent validation using shRNA and CRISPR-Cas9 confirmed MAP2K1 dependency. In vitro and in vivo inhibitor studies established that NCI-H1437 cells are sensitive to MEK1 inhibitors, including the FDA-approved drug trametinib. Like NCI-H1437 cells, the MAP2K1-mutant cell lines SNU-C1 (colon) and OCUM-1 (gastric) showed decreased viability after MAP2K1 depletion via Cas9-mediated gene editing. Similarly, these cell lines were particularly sensitive to trametinib treatment compared with control cell lines. On the basis of these data, cancers that harbor driver mutations in MAP2K1 could benefit from treatment with MEK1 inhibitors. Furthermore, this functional data mining approach provides a general method to experimentally test genomic features that confer dependence in tumors.. Cancers with an activated RAS/MAPK pathway driven by oncogenic MAP2K1 mutations may be particularly sensitive to MEK1 inhibitor treatments.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Cell Line, Tumor; Cell Survival; Computational Biology; Drug Delivery Systems; Humans; Lung Neoplasms; MAP Kinase Kinase 1; Mice; Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; RNA Interference; Xenograft Model Antitumor Assays

2016
The HSP90 inhibitor, NVP-AUY922, sensitizes KRAS-mutant non-small cell lung cancer with intrinsic resistance to MEK inhibitor, trametinib.
    Cancer letters, 2016, Mar-01, Volume: 372, Issue:1

    RAS-driven tumors are often difficult to treat with conventional therapies and therefore, novel treatment strategies are necessary. The present study describes a promising targeted therapeutic strategy against non-small cell lung cancer (NSCLC) harboring KRAS mutations, which has intrinsic resistance to MEK inhibition. Results showed that intrinsic resistance to MEK inhibition occurred via high AKT expression by PI3K activation as a bypass pathway. The HSP90 inhibitor AUY922 suppressed PI3K-AKT-mTOR and RAF-MEK-ERK, and rendered cells sensitive to trametinib (GSK1120212). Synergy from the combination of the two drugs was observed in only sub-therapeutic concentrations of either drug. Dual inhibition of the HSP90 and MEK signaling pathways with sub-therapeutic doses may represent a potent therapeutic strategy to treat KRAS-mutant NSCLC with intrinsic resistance to MEK inhibition and to resolve the toxicity observed upon dual inhibition of AKT and MEK at therapeutic doses in clinical trials.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Female; HSP90 Heat-Shock Proteins; Humans; Isoxazoles; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Resorcinols; Signal Transduction; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays

2016
Coadministration of Trametinib and Palbociclib Radiosensitizes KRAS-Mutant Non-Small Cell Lung Cancers In Vitro and In Vivo.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2016, Jan-01, Volume: 22, Issue:1

    To investigate the potential roles that p16 (CDKN2A) and RB activation have in sensitization to MEK inhibitor in resistant KRAS-mutant non-small cell lung cancer cells (NSCLC) in vitro and in vivo.. Cell viability was measured with MTS assays. Effects of administration of radiation and combination drug treatments were evaluated by clonogenic assay, flow cytometry, and Western blots. DNA repair was assessed using immunofluorescent analysis. Finally, lung cancer xenografts were used to examine in vivo effects of drug treatment and radiation therapy.. In this study, we showed that sensitivity to MEK inhibitor correlated to the RB/p16/CDK4 pathway and knockdown of RB induced resistance in cell lines sensitive to MEK inhibitor. Also, overexpression of p16 and inhibition of CDK4 had the ability to sensitize normally resistant cell lines. Our data indicated that the MEK inhibitor (trametinib, GSK112012) cooperated with the CDK4/6 inhibitor (palbociclib, PD0332991) to strongly reduce cell viability of KRAS-mutant NSCLCs that were resistant to the MEK inhibitor in vitro and in vivo. In addition, we report for the first time that resistance of KRAS-mutant NSCLCs to MEK inhibitor is, at least partly, due to p16 mutation status, and we described a drug combination that efficiently reactivates the RB tumor suppressor pathway to trigger radiosensitizing effects, apoptosis, and cell-cycle arrest.. Our findings suggest that MEK inhibitor in combination with CDK4/6 inhibitor has significant anti-KRAS-mutant NSCLC activity and radiosensitizing effect in preclinical models, potentially providing a novel therapeutic strategy for patients with advanced KRAS-mutant NSCLCs.

    Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p16; Disease Models, Animal; DNA Repair; Drug Synergism; Female; Humans; Lung Neoplasms; Mutation; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Pyridones; Pyrimidinones; Radiation Tolerance; Radiation-Sensitizing Agents; ras Proteins; Retinoblastoma Protein; Xenograft Model Antitumor Assays

2016
BRAF inhibition for advanced locoregional BRAF V600E mutant melanoma: a potential neoadjuvant strategy.
    Melanoma research, 2016, Volume: 26, Issue:1

    Selective BRAF inhibitors (BRAFi) yield objective responses in 50% of patients with metastatic BRAF V600E mutant melanoma. Adding an MEK inhibitor increases this response rate to 70%. Limited data are available on the outcomes of unresectable stage III patients, and it remains unclear whether BRAF-targeted therapy can be utilized as a neoadjuvant strategy. Data on patients with advanced locoregional BRAF V600E mutant melanoma treated with BRAF-targeted therapy at Moffitt Cancer Center were analyzed to determine response rates, subsequent resection rates after tumor downsizing, pathologic responses, and patient survival. Fifteen patients with locoregional disease treated with BRAF-targeted therapy, either BRAFi alone (vemurafenib; 11 patients) or a combination of BRAFi and an MEK inhibitor (dabrafenib plus trametinib or placebo; four patients), were identified. The median age was 50 years; the median follow-up was 25.4 months. The median BRAF-targeted therapy treatment duration was 6.0 months (range 1.2-29.4 months). Response Evaluation Criteria In Solid Tumors-based evaluation demonstrated objective response in 11 patients (73.3%). Six patients underwent resection of the remaining disease after therapy. Pathological analysis showed complete pathologic response (n=2), partial pathologic response (n=2), or no pathologic response (n=2). Four of six patients undergoing surgery have been alive for more than 2 years, including three patients currently free from active disease. No complications attributable to BRAF-targeted therapy were observed in the perioperative period. Dose reduction or discontinuation because of toxicities occurred in 10/15 patients. Neoadjuvant BRAF-targeted therapy may be effective in advanced locoregional BRAF V600E mutant melanoma patients in increasing resectability, yielding pathological responses, and achieving prolonged survival.

    Topics: Amino Acid Substitution; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Follow-Up Studies; Glutamic Acid; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation, Missense; Neoadjuvant Therapy; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Sulfonamides; Treatment Outcome; Valine; Vemurafenib

2016
Treatment of ameloblastoma and ameloblastic carcinoma with radiotherapy.
    European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery, 2016, Volume: 273, Issue:10

    The purpose of this study is to report our institutional experience using radiotherapy in the treatment of ameloblastoma and ameloblastic carcinoma. Three patients with ameloblastoma and 3 patients with ameloblastic carcinoma were treated with radiotherapy alone (2 patients) or surgery and postoperative radiotherapy (4 patients) at the University of Florida between 1973 and 2007. Follow-up ranged from 4.0 to 13.1 years with a median of 7.8 years. Radiotherapy complications were scored using the Common Terminology Criteria for Adverse Events, version 4.0. Local control was achieved in 4 of the 6 patients. One patient treated with RT alone for an unresectable ameloblastoma developed a local recurrence and metastases in both the cervical lymph nodes and lungs, but had excellent response to dual BRAF/MEK inhibition with dabrafenib and trametinib. Another patient treated with surgery and postoperative radiotherapy for an ameloblastic carcinoma recurred locally without metastasis, but was not salvaged. No significant treatment-related complications were observed. For patients with local recurrence or inadequate margins after surgery, adjuvant radiotherapy provides the potential for disease control. In the setting of metastatic disease, targeted therapies may provide an additional opportunity for salvage.

    Topics: Adult; Aged; Ameloblastoma; Antineoplastic Agents; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Imidazoles; Long Term Adverse Effects; Male; Middle Aged; Neck Dissection; Neoplasm Recurrence, Local; Outcome and Process Assessment, Health Care; Oximes; Pyridones; Pyrimidinones; Radiotherapy, Adjuvant

2016
Parthenolide induces MITF-M downregulation and senescence in patient-derived MITF-M(high) melanoma cell populations.
    Oncotarget, 2016, Feb-23, Volume: 7, Issue:8

    The activity of the M isoform of microphthalmia-associated transcription factor (MITF-M) has been attributed to regulation of differentiation, proliferation, survival and senescence of melanoma cells. MITF expression was shown to be antagonized by the activation of transcription factor NF-κB. Parthenolide, an inhibitor of NF-κB, has not been yet reported to affect MITF-M expression. Our results obtained in patient-derived melanoma cell populations indicate that parthenolide efficiently decreases the MITF-M level. This is neither dependent on p65/NF-κB signaling nor RAF/MEK/ERK pathway activity as inhibition of MEK by GSK1120212 (trametinib) and induction of ERK1/2 activity by parthenolide itself do not interfere with parthenolide-triggered depletion of MITF-M in both wild-type BRAF and BRAF(V600E) melanoma populations. Parthenolide activity is not prevented by inhibitors of caspases, proteasomal and lysosomal pathways. As parthenolide reduces MITF-M transcript level and HDAC1 protein level, parthenolide-activated depletion of MITF-M protein may be considered as a result of transcriptional regulation, however, the influence of parthenolide on other elements of a dynamic control over MITF-M cannot be ruled out. Parthenolide induces diverse effects in melanoma cells, from death to senescence. The mode of the response to parthenolide is bound to the molecular characteristics of melanoma cells, particularly to the basal MITF-M expression level but other cell-autonomous differences such as NF-κB activity and MCL-1 level might also contribute. Our data suggest that parthenolide can be developed as a drug used in combination therapy against melanoma when simultaneous inhibition of MITF-M, NF-κB and HDAC1 is needed.

    Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Down-Regulation; Extracellular Signal-Regulated MAP Kinases; Histone Deacetylase 1; Humans; MAP Kinase Signaling System; Melanoma; Microphthalmia-Associated Transcription Factor; Myeloid Cell Leukemia Sequence 1 Protein; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sesquiterpenes; Transcription Factor RelA; Tumor Cells, Cultured

2016
Treating leukemia at the risk of inducing severe anemia.
    Experimental hematology, 2016, Volume: 44, Issue:5

    Anemia is a frequently observed adverse effect in cancer patients who receive chemotherapy or drugs designed to block specific oncogenic signaling pathways, although the underlying mechanisms are poorly understood. An article first published online (Zhu HH, Luo X, Zhang K, et al. Proc Natl Acad Sci USA 2015;112:13342-13347) presented data indicating that cell type-specific pathway cross-talk is likely an important mechanism to consider. Shp2 and Pten, two master regulators of central cytoplasmic signaling pathways, oppose each other in myeloproliferation and leukemogenesis, but cooperate in promoting erythropoiesis. Thus, genetic ablation or pharmacologic inhibition of Shp2 suppresses the leukemogenic effect of Pten loss, yet simultaneously induces severe anemia in mice with Pten deficiency in blood cells.

    Topics: Anemia; Animals; Enzyme Inhibitors; Erythropoiesis; Leukemia; Mice; Mice, Knockout; Models, Genetic; Mutation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; PTEN Phosphohydrolase; Pyridones; Pyrimidinones; Risk Factors; Signal Transduction

2016
Drosophila Lung Cancer Models Identify Trametinib plus Statin as Candidate Therapeutic.
    Cell reports, 2016, Feb-16, Volume: 14, Issue:6

    We have developed a Drosophila lung cancer model by targeting Ras1(G12V)--alone or in combination with PTEN knockdown--to the Drosophila tracheal system. This led to overproliferation of tracheal tissue, formation of tumor-like growths, and animal lethality. Screening a library of FDA-approved drugs identified several that improved overall animal survival. We explored two hits: the MEK inhibitor trametinib and the HMG-CoA reductase inhibitor fluvastatin. Oral administration of these drugs inhibited Ras and PI3K pathway activity, respectively; in addition, fluvastatin inhibited protein prenylation downstream of HMG-CoA reductase to promote survival. Combining drugs led to synergistic suppression of tumor formation and rescue lethality; similar synergy was observed in human A549 lung adenocarcinoma cells. Notably, fluvastatin acted both within transformed cells and also to reduce whole-body trametinib toxicity in flies. Our work supports and provides further context for exploring the potential of combining statins with MAPK inhibitors such as trametinib to improve overall therapeutic index.

    Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Drosophila melanogaster; Drosophila Proteins; Drug Combinations; Drug Screening Assays, Antitumor; Drug Synergism; Fatty Acids, Monounsaturated; Fluvastatin; Gene Expression Regulation, Neoplastic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; IMP Dehydrogenase; Indoles; Lung Neoplasms; Protein Kinase Inhibitors; PTEN Phosphohydrolase; Pyridones; Pyrimidinones; Signal Transduction; Survival Rate

2016
Adjuvant Trametinib Delays the Outgrowth of Occult Pancreatic Cancer in a Mouse Model of Patient-Derived Liver Metastasis.
    Annals of surgical oncology, 2016, Volume: 23, Issue:6

    Most patients with pancreatic ductal adenocarcinoma (PDAC) die within 5 years following resection plus adjuvant gemcitabine (Gem) from outgrowth of occult metastases. We hypothesized that inhibition of the KRAS pathway with the MEK inhibitor trametinib would inhibit the outgrowth of occult liver metastases in a preclinical model.. Liver metastases harvested from two patients with PDAC (Tumors 608, 366) were implanted orthotopically in mice. Tumor cell lines were derived and transduced with lentiviruses encoding luciferase and injected into spleens of mice generating microscopic liver metastases. Growth kinetics of liver metastases were measured with bioluminescent imaging and time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS) were determined.. Trametinib (0.3 mg/kg BID) significantly prolonged OS versus control (Tumor 608: 114 vs. 43 days, p < 0.001; Tumor 366: not reached vs. 167 days, p = 0.0488). In vivo target validation demonstrated trametinib significantly reduced phosphorylated-ERK and expression of the ERK-responsive gene DUSP6. In a randomized, preclinical trial, mice were randomized to: (1) control, (2) adjuvant Gem (100 mg/kg IP, Q3 days) × 7 days followed by surveillance, or (3) adjuvant Gem followed by trametinib. Sequential Gem-trametinib significantly decreased metastatic cell outgrowth and increased TTP and PFS.. Treatment of mice bearing micrometastases with trametinib significantly delayed tumor outgrowth by effectively inhibiting KRAS-MEK-ERK signaling. In a randomized, preclinical, murine trial adjuvant sequential Gem followed by trametinib inhibited occult metastatic cell outgrowth in the liver and increased PFS versus adjuvant Gem alone. An adjuvant trial of sequential Gem-trametinib is being planned in patients with resected PDAC.

    Topics: Animals; Carcinoma, Pancreatic Ductal; Humans; Liver Neoplasms; Mice; Pancreatic Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2016
A synthetic-lethality RNAi screen reveals an ERK-mTOR co-targeting pro-apoptotic switch in PIK3CA+ oral cancers.
    Oncotarget, 2016, Mar-08, Volume: 7, Issue:10

    mTOR inhibition has emerged as a promising strategy for head and neck squamous cell carcinomas (HNSCC) treatment. However, most targeted therapies ultimately develop resistance due to the activation of adaptive survival signaling mechanisms limiting the activity of targeted agents. Thus, co-targeting key adaptive mechanisms may enable more effective cancer cell killing. Here, we performed a synthetic lethality screen using shRNA libraries to identify druggable candidates for combinatorial signal inhibition. We found that the ERK pathway was the most highly represented. Combination of rapamycin with trametinib, a MEK1/2 inhibitor, demonstrated strong synergism in HNSCC-derived cells in vitro and in vivo, including HNSCC cells expressing the HRAS and PIK3CA oncogenes. Interestingly, cleaved caspase-3 was potently induced by the combination therapy in PIK3CA+ cells in vitro and tumor xenografts. Moreover, ectopic expression of PIK3CA mutations into PIK3CA- HNSCC cells sensitized them to the pro-apoptotic activity of the combination therapy. These findings indicate that co-targeting the mTOR/ERK pathways may provide a suitable precision strategy for HNSCC treatment. Moreover, PIK3CA+ HNSCC are particularly prone to undergo apoptosis after mTOR and ERK inhibition, thereby providing a potential biomarker of predictive value for the selection of patients that may benefit from this combination therapy.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Class I Phosphatidylinositol 3-Kinases; Drug Synergism; Female; Heterografts; Humans; MAP Kinase Signaling System; Mice; Mice, Nude; Molecular Targeted Therapy; Mouth Neoplasms; Pyridones; Pyrimidinones; RNA Interference; Sirolimus; TOR Serine-Threonine Kinases

2016
Initial experience with combined BRAF and MEK inhibition with stereotactic radiosurgery for BRAF mutant melanoma brain metastases.
    Melanoma research, 2016, Volume: 26, Issue:4

    The combined use of the BRAF inhibitor dabrafenib and MEK inhibitor trametinib has been found to improve survival over dabrafenib alone. The management of melanoma brain metastases continues to present challenges. In this study, we report our initial experience in the management of melanoma brain metastases with stereotactic radiosurgery (SRS) with the use of BRAF and MEK inhibitors. We identified six patients treated with SRS for 17 brain metastases within 3 months of BRAF and MEK inhibitor administration. The median planning target volume was 0.42 cm (range: 0.078-2.08 cm). The median treatment dose was 21 Gy (range 18-24 Gy). The median follow-up of all lesions from SRS was 10.6 months (range 5.8-28.5 months). One lesion was found to undergo local failure 21.7 months following SRS treatment. The median overall survival was 20.0 months (range 6.1-31.8 months) from the time of SRS treatment and 23.1 months (range: 12.1-30.9 months) from the date of BRAFi and MEKi administration. There was no evidence of increased nor unexpected toxicity with the two modalities combined. In this initial experience of melanoma brain metastases treated with BRAF and MEK inhibition with SRS, we find the two modalities can be combined safely. These outcomes should be assessed further in prospective evaluations.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemoradiotherapy; Female; Humans; Imidazoles; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiosurgery; Skin Neoplasms

2016
IL15 Agonists Overcome the Immunosuppressive Effects of MEK Inhibitors.
    Cancer research, 2016, 05-01, Volume: 76, Issue:9

    Many signal transduction inhibitors are being developed for cancer therapy target pathways that are also important for the proper function of antitumor lymphocytes, possibly weakening their therapeutic effects. Here we show that most inhibitors targeting multiple signaling pathways have especially strong negative effects on T-cell activation at their active doses on cancer cells. In particular, we found that recently approved MEK inhibitors displayed potent suppressive effects on T cells in vitro However, these effects could be attenuated by certain cytokines that can be administered to cancer patients. Among them, clinically available IL15 superagonists, which can activate PI3K selectively in T lymphocytes, synergized with MEK inhibitors in vivo to elicit potent and durable antitumor responses, including by a vaccine-like effect that generated resistance to tumor rechallenge. Our work identifies a clinically actionable approach to overcome the T-cell-suppressive effects of MEK inhibitors and illustrates how to reconcile the deficiencies of signal transduction inhibitors, which impede desired immunologic effects in vivo Cancer Res; 76(9); 2561-72. ©2016 AACR.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Flow Cytometry; High-Throughput Screening Assays; Humans; Interleukin-15; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms, Experimental; Protein Kinase Inhibitors; Proteins; Pyridones; Pyrimidinones; Recombinant Fusion Proteins; Signal Transduction; Xenograft Model Antitumor Assays

2016
Dual Targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells.
    Molecular cancer therapeutics, 2016, Volume: 15, Issue:6

    Inhibitors of the bromodomain and extraterminal domain (BET) protein family attenuate the proliferation of several tumor cell lines. These effects are mediated, at least in part, through repression of c-MYC. In colorectal cancer, overexpression of c-MYC due to hyperactive WNT/β-catenin/TCF signaling is a key driver of tumor progression; however, effective strategies to target this oncogene remain elusive. Here, we investigated the effect of BET inhibitors (BETi) on colorectal cancer cell proliferation and c-MYC expression. Treatment of 20 colorectal cancer cell lines with the BETi JQ1 identified a subset of highly sensitive lines. JQ1 sensitivity was higher in cell lines with microsatellite instability but was not associated with the CpG island methylator phenotype, c-MYC expression or amplification status, BET protein expression, or mutation status of TP53, KRAS/BRAF, or PIK3CA/PTEN Conversely, JQ1 sensitivity correlated significantly with the magnitude of c-MYC mRNA and protein repression. JQ1-mediated c-MYC repression was not due to generalized attenuation of β-catenin/TCF-mediated transcription, as JQ1 had minimal effects on other β-catenin/TCF target genes or β-catenin/TCF reporter activity. BETi preferentially target super-enhancer-regulated genes, and a super-enhancer in c-MYC was recently identified in HCT116 cells to which BRD4 and effector transcription factors of the WNT/β-catenin/TCF and MEK/ERK pathways are recruited. Combined targeting of c-MYC with JQ1 and inhibitors of these pathways additively repressed c-MYC and proliferation of HCT116 cells. These findings demonstrate that BETi downregulate c-MYC expression and inhibit colorectal cancer cell proliferation and identify strategies for enhancing the effects of BETi on c-MYC repression by combinatorial targeting the c-MYC super-enhancer. Mol Cancer Ther; 15(6); 1217-26. ©2016 AACR.

    Topics: Animals; Azepines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Drug Synergism; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; MAP Kinase Signaling System; Mice; Neoplasm Transplantation; Proto-Oncogene Proteins c-myc; Pyridones; Pyrimidinones; Triazoles; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

2016
Delayed Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Inhibition by Trametinib Attenuates Systemic Inflammatory Responses and Multiple Organ Injury in Murine Sepsis.
    Critical care medicine, 2016, Volume: 44, Issue:8

    The mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway is an essential component of innate immunity necessary for mediating proinflammatory responses in the setting of sepsis. We previously demonstrated that the mitogen-activated protein kinase 1/2 inhibitor trametinib prevents endotoxin-induced renal injury in mice. We therefore assessed efficacy of trametinib in a more clinically relevant experimental model of sepsis.. Controlled in vivo laboratory study.. University animal research laboratory.. Male C57BL/6 mice.. Mice were subjected to cecal ligation and puncture to induce sepsis or underwent sham operation as controls. Six hours after cecal ligation and puncture, mice were randomized to four experimental groups as follows: 1) sham control; 2) sham control + trametinib (1 mg/kg, IP); 3) cecal ligation and puncture; and 4) cecal ligation and puncture + trametinib. All animals received buprenorphine (0.05 mg/kg, SC) and imipenem/cilastatin (14 mg/kg, SC) in 1.5 mL of warm saline (40 mL/kg) at the 6-hour time point. Mice were euthanized at 18 hours after induction of cecal ligation and puncture.. Trametinib inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase signaling 6 hours after cecal ligation and puncture attenuated increases in circulating proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, interleukin-6, and granulocyte macrophage colony-stimulating factor) and hypothermia at 18 hours. Trametinib also attenuated multiple organ injury as determined by serum creatinine, alanine aminotransferase, lactate dehydrogenase, and creatine kinase. At the organ level, trametinib completely restored peritubular capillary perfusion in the kidney. Restoration of microvascular perfusion was associated with reduced messenger RNA expression of well-characterized markers of proximal tubule injury. mitogen-activated protein kinase/extracellular signal-regulated kinase blockade attenuated cecal ligation and puncture-mediated up-regulation of cytokines (tumor necrosis factor-α, interleukin-1β) and restored interleukin-6 to control levels in the renal cortex, indicating the protective effects on the proximal tubule occur primarily through modulation of the proinflammatory response in sepsis.. These data reveal that the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor trametinib attenuates systemic inflammation and multiple organ damage in a clinically relevant model of sepsis. Because trametinib has been safely used in humans, we propose that this drug might represent a translatable approach to limit organ injury in septic patients.

    Topics: Acute Kidney Injury; Animals; Cytokines; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Inflammation; Inflammation Mediators; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; Multiple Organ Failure; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; RNA, Messenger; Sepsis

2016
Functional and genetic screening of acute myeloid leukemia associated with mediastinal germ cell tumor identifies MEK inhibitor as an active clinical agent.
    Journal of hematology & oncology, 2016, Mar-31, Volume: 9

    Hematologic malignancies arising in the setting of established germ cell tumors have been previously described and have a dismal prognosis. Identification of targetable mutations and pathway dysregulation through massively parallel sequencing and functional assays provides new approaches to disease management.. Herein, we report the case of a 23-year-old male who was diagnosed with a mediastinal germ cell tumor and subsequent acute myeloid leukemia. A shared clonal origin was demonstrated through identification of identical NRAS and TP53 somatic mutations in both malignancies. The patient's leukemia was refractory to standard therapies with short interval relapse. Functional assays demonstrated the patient's blasts to be sensitive to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, correlating with the activating NRAS mutation. The patient experienced a sustained partial remission while on trametinib therapy but ultimately suffered relapse of the germ cell tumor. The leukemic clone remained stable and sensitive to trametinib at that time.. This case highlights the potential power of combining genetic sequencing and in vitro functional assays with targeted therapies in the treatment of rare diseases.

    Topics: Acute Disease; GTP Phosphohydrolases; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Myeloid; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mediastinal Neoplasms; Membrane Proteins; Neoplasm Recurrence, Local; Neoplasms, Germ Cell and Embryonal; Point Mutation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Treatment Outcome; Tumor Suppressor Protein p53; Young Adult

2016
BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors.
    Cell death & disease, 2016, Apr-07, Volume: 7

    B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disease that kills ~50% of adult patients. With the exception of some BCR-ABL1(+) patients who benefit from tyrosine kinase inhibitors, there are no effective targeted therapies for adult B-ALL patients and chemotherapy remains first-line therapy despite adverse side effects and poor efficacy. We show that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition does not suppress B-ALL cell growth. However, MEK inhibition synergized with BCL-2/BCL-XL family inhibitors to suppress proliferation and induce apoptosis in B-ALL cells. We show that this synergism is mediated by the pro-apoptotic factor BIM, which is dephosphorylated as a result of MEK inhibition, allowing it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death. This cooperative effect is observed in B-ALL cells driven by a range of genetic abnormalities and therefore has significant therapeutic potential.

    Topics: Aniline Compounds; Animals; Apoptosis; B-Lymphocytes; Bcl-2-Like Protein 11; bcl-X Protein; Cell Line, Tumor; Cell Proliferation; Female; Humans; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyridones; Pyrimidinones; RNA Interference; Sulfonamides; Thioglycolates

2016
Simultaneous quantification of dabrafenib and trametinib in human plasma using high-performance liquid chromatography-tandem mass spectrometry.
    Journal of pharmaceutical and biomedical analysis, 2016, Jun-05, Volume: 125

    Dabrafenib (Tafinlar(®)) and trametinib (Mekinist(®)) are registered for the treatment of patients with BRAF V600 mutation positive unresectable or metastatic melanoma. To support therapeutic drug monitoring (TDM) and clinical pharmacological trials, an assay to simultaneously quantify dabrafenib and trametinib in human plasma using liquid chromatography tandem mass spectrometry was developed and validated. Human plasma samples were collected on an outpatient base and stored at nominally -20°C. Analytes and internal standards (stable isotope labeled compounds) were extracted with TBME. After snap freezing the samples in a dry ice-ethanol bath, the organic layer was transferred to a clean tube and evaporated under a gentle stream of nitrogen gas. The dry extract was then reconstituted with 100μL acetonitrile and 5μL of the final extract was injected and separated on a C18 column with gradient elution, and analyzed with triple quadrupole mass spectrometry in positive-ion mode. The validated assay ranges from 50 to 5000ng/mL for dabrafenib and 0.5-50ng/mL for trametinib were linear, and correlation coefficient (r(2)) of 0.996 or better. At all concentrations of both analytes the biases were within ±15% of the nominal concentrations and precisions were ≤15%. All results were within the acceptance criteria of the latest US FDA guidance and EMA guidelines on method validation. Dabrafenib was found to degrade under the influence of light in different organic solvents and at least seven degradation products were detected. In conclusion, the described method to simultaneously quantify dabrafenib and trametinib in human plasma was successfully validated and applied for therapeutic drug monitoring in cancer patients treated with dabrafenib and trametinib.

    Topics: Calibration; Chromatography, High Pressure Liquid; Humans; Imidazoles; Limit of Detection; Oximes; Pyridones; Pyrimidinones; Reproducibility of Results; Tandem Mass Spectrometry

2016
Preclinical exploration of combining plasmacytoid and myeloid dendritic cell vaccination with BRAF inhibition.
    Journal of translational medicine, 2016, Apr-14, Volume: 14

    Melanoma is the most lethal type of skin cancer and its incidence is progressively increasing. The introductions of immunotherapy and targeted therapies have tremendously improved the treatment of melanoma. Selective inhibition of BRAF by vemurafenib results in objective clinical responses in around 50 % of patients suffering from BRAFV600 mutated melanoma. However, drug resistance often results in hampering long-term tumor control. Alternatively, immunotherapy by vaccination with natural dendritic cells (nDCs) demonstrated long-term tumor control in a proportion of patients. We postulate that the rapid tumor debulking by vemurafenib can synergize the long-term tumor control of nDC vaccination to result in an effective treatment modality in a large proportion of patients. Here, we investigated the feasibility of this combination by analyzing the effect of vemurafenib on the functionality of nDCs.. Plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were isolated from PBMCs obtained from buffy coats from healthy volunteers or vemurafenib-treated melanoma patients. Maturation of pDCs, mDCs and immature monocyte-derived DCs was induced by R848 in the presence or absence of vemurafenib and analyzed by FACS. Cytokine production and T cell proliferation induced by mature DCs were analyzed.. Vemurafenib inhibited maturation and cytokine production of highly purified nDCs of healthy volunteers resulting in diminished allogeneic T cell proliferation. This deleterious effect of vemurafenib on nDC functionality was absent when total PBMCs were exposed to vemurafenib. In patients receiving vemurafenib, nDC functionality and T cell allostimulatory capacity were unaffected.. Although vemurafenib inhibited the functionality of purified nDC of healthy volunteers, this effect was not observed when nDCs were matured in the complete PBMC fraction. This might have been caused by increased vemurafenib uptake in absence of other cell types. In accordance, nDCs isolated from patients on active vemurafenib treatment showed no negative effects. In conclusion, our results pave the way for a combinatorial treatment strategy and, we propose that combining vemurafenib with nDC vaccination represent a powerful opportunity that deserves more investigation in the clinic.

    Topics: Antigen Presentation; Antigens, Neoplasm; Biological Availability; Cell Differentiation; Cell Separation; Cytokines; Dendritic Cells; Down-Regulation; Humans; Indoles; Lymphocyte Activation; Melanoma; Myeloid Cells; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vaccination; Vemurafenib

2016
MEK inhibitor treatment is effective in a patient with metastatic carcinoma of the ampulla of Vater with BRAF and NRAS mutations shown by next-generation sequencing.
    Anti-cancer drugs, 2016, Volume: 27, Issue:6

    Here, we present a case of an 84-year-old woman who developed obstructive jaundice and was diagnosed with nonoperable adenocarcinoma originating from the ampulla of Vater, a lethal disease with a median overall survival of less than a year. Her tumor was examined by next-generation sequencing, which showed BRAF and NRAS mutations. To target these mutations, a MEK inhibitor was chosen for treatment. The patient has been treated with a MEK inhibitor for the last 12 months since diagnosis, with clinical and laboratory improvement and manageable side effects. PET-computed tomography imaging has shown stable disease or improvement in the primary and metastatic lesions. This is the first case report of an ampulla of a Vater cancer patient with NRAS and BRAF mutations, identified in next-generation sequencing, and treated successfully with a MEK inhibitor.

    Topics: Aged, 80 and over; Ampulla of Vater; Common Bile Duct Neoplasms; Female; GTP Phosphohydrolases; High-Throughput Nucleotide Sequencing; Humans; MAP Kinase Kinase Kinases; Membrane Proteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2016
[The Role of BRAF/MEK Inhibition in Metastatic Malignant Melanoma - a Case Study].
    Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti, 2016, Volume: 29, Issue:2

    Metastatic malignant melanoma belongs to a group of cancers with high mortality. In recent years, advances in our knowledge of the pathogenesis of melanoma and the discovery of new drugs has resulted in significant progress in the treatment of metastatic malignant melanoma patients. The development of resistance to these drugs, however, remains a challenge. One way how to avoid resistance, or at least delay it, is to administer combination therapy.. This case study demonstrates that combination therapy with a BRAF and a MEK inhibitor can be used to successfully treat metastatic malignant melanoma patients and suggests they should be employed in therapeutic algorithms for patients with metastatic malignant melanoma and BRAF gene mutations.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Neoplasm Metastasis; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2016
Quantitative assessment of BRAF V600 mutant circulating cell-free tumor DNA as a tool for therapeutic monitoring in metastatic melanoma patients treated with BRAF/MEK inhibitors.
    Journal of translational medicine, 2016, Apr-19, Volume: 14

    BRAF V600 mutant circulating cell-free tumor DNA (BRAF V600mut ctDNA) could serve as a specific biomarker in patients with BRAF V600 mutant melanoma. We analyzed the value of BRAF V600mut ctDNA from plasma as a monitoring tool for advanced melanoma patients treated with BRAF/MEK inhibitors.. Allele-specific quantitative PCR analysis for BRAF V600 E/E2/D/K/R/M mutations was performed on DNA extracted from plasma of patients with known BRAF V600 mutant melanoma who were treated with dabrafenib and trametinib.. 245 plasma samples from 36 patients were analyzed. In 16 patients the first plasma sample was obtained before the first dosing of dabrafenib/trametinib. At baseline, BRAF V600mut ctDNA was detected in 75 % of patients (n = 12/16). BRAF V600mut ctDNA decreased rapidly upon initiation of targeted therapy (p < 0.001) and became undetectable in 60 % of patients (n = 7/12) after 6 weeks of treatment. During treatment, disease progression (PD) was diagnosed in 27 of 36 patients. An increase of the BRAF V600mut ctDNA copy number and fraction, identified PD with a sensitivity of 70 % (n = 19/27) and a specificity of 100 %. An increase in the BRAF V600mut ctDNA fraction was detected prior to clinical PD in 44 % of cases (n = 12/27) and simultaneously with PD in 26 % of patients (n = 7/27).. Quantitative analysis of BRAF V600mut ctDNA in plasma has unique features as a monitoring tool during treatment with BRAF/MEK inhibitors. Its potential as an early predictor of acquired resistance deserves further evaluation.

    Topics: Cell-Free System; Disease Progression; DNA, Neoplasm; Drug Monitoring; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Mutation; Neoplastic Cells, Circulating; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2016
The EGFR-specific antibody cetuximab combined with chemotherapy triggers immunogenic cell death.
    Nature medicine, 2016, Volume: 22, Issue:6

    Cetuximab is a monoclonal antibody that is effective in the treatment of metastatic colorectal cancer (mCRC). Cetuximab blocks epidermal growth factor receptor (EGFR)-ligand interaction and inhibits downstream RAS-ERK activation. However, only some activating mutations in RAS affect cetuximab efficacy, and it is not clear what else mediates treatment success. Here we hypothesized that cetuximab induces immunogenic cell death (ICD) that activates a potent antitumor response. We found that cetuximab, in combination with chemotherapy, fostered ICD in CRC cells, which we measured via the endoplasmic reticulum (ER) stress response and an increase in phagocytosis by dendritic cells. ICD induction depended on the mutational status of the EGFR signaling pathway and on the inhibition of the splicing of X-box binding protein 1 (XBP1), an unfolded protein response (UPR) mediator. We confirmed the enhanced immunogenicity elicited by cetuximab in a mouse model of human EGFR-expressing CRC. Overall, we demonstrate a new, immune-related mechanism of action of cetuximab that may help to tailor personalized medicine.

    Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Calreticulin; Camptothecin; Cell Death; Cell Line, Tumor; Cetuximab; Colorectal Neoplasms; Dendritic Cells; Disease Models, Animal; Endoplasmic Reticulum Stress; Fluorouracil; HCT116 Cells; HT29 Cells; Humans; Indoles; Irinotecan; Leucovorin; Mice; Panitumumab; Phagocytosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Sulfonamides; Unfolded Protein Response; Vemurafenib; X-Box Binding Protein 1

2016
SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells.
    Oncotarget, 2016, Jun-07, Volume: 7, Issue:23

    Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 - a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Female; Heterocyclic Compounds, 3-Ring; Humans; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Pancreatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; RNA Interference; RNA, Small Interfering; SOXB1 Transcription Factors

2016
[Response of BRAF(L597Q)-mutant melanoma to trametinib : Targeted melanoma therapy beyond BRAF(V600) mutations].
    Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete, 2016, Volume: 67, Issue:8

    Approximately 7 % of melanomas have a BRAF mutation beyond codon 600. These mutations can be BRAF activating without being addressable by an approved BRAF inhibitor. The case of a patient with fulminant metastatic melanoma and a BRAF(L597Q) mutation is presented. It is demonstrated that the tumor shows an excellent response to the MEK inhibitor trametinib. This is an example for possible targeted therapy in a non-V600-mutated melanoma resulting in a 17-month overall survival.

    Topics: Antineoplastic Agents; Humans; Male; Melanoma; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2016
Dabrafenib Active in Rare NSCLC Subtype.
    Cancer discovery, 2016, Volume: 6, Issue:7

    Results from a phase II trial show that the BRAF inhibitor dabrafenib has significant single-agent activity in patients with advanced non-small cell lung cancer harboring the BRAF V600E mutation. However, data from another arm of the study suggest that combining dabrafenib with a MEK inhibitor may be a more effective treatment strategy for these patients.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Disease-Free Survival; Humans; Imidazoles; Lung Neoplasms; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

2016
Genomic profiling and directed ex vivo drug analysis of an unclassifiable myelodysplastic/myeloproliferative neoplasm progressing into acute myeloid leukemia.
    Genes, chromosomes & cancer, 2016, Volume: 55, Issue:11

    Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are rare genetically heterogeneous hematologic diseases associated with older age and a poor prognosis. If the disease progresses into acute myeloid leukemia (AML), it is often refractory to treatment. To gain insight into genetic alterations associated with disease progression, whole exome sequencing and single nucleotide polymorphism arrays were used to characterize the bone marrow and blood samples from a 39-year-old woman at MDS/MPN-U diagnosis and at AML progression, in which routine genetic diagnostics had not identified any genetic alterations. The data revealed the presence of a partial tandem duplication of the MLL gene as the only detectable copy number change and 11 non-silent somatic mutations, including DNMT3A R882H and NRAS G13D. All somatic lesions were present both at initial MDS/MPN-U diagnosis and at AML presentation at similar mutant allele frequencies. The patient has since had two extramedullary relapses and is at high risk of a future bone marrow relapse. A directed ex vivo drug sensitivity analysis showed that the patient's AML cells are sensitive to, for example, the MEK inhibitor trametinib and the proteasome inhibitor bortezomib, indicating that she may benefit from treatment with these drugs. © 2016 Wiley Periodicals, Inc.

    Topics: Adult; Bortezomib; Disease Progression; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Female; Gene Duplication; Gene Frequency; Genetic Heterogeneity; Genome, Human; GTP Phosphohydrolases; Histone-Lysine N-Methyltransferase; Humans; Leukemia, Myeloid, Acute; Membrane Proteins; Mutation; Myelodysplastic Syndromes; Myeloid-Lymphoid Leukemia Protein; Pyridones; Pyrimidinones

2016
MEK Is a Therapeutic and Chemopreventative Target in Squamous Cell Carcinoma.
    The Journal of investigative dermatology, 2016, Volume: 136, Issue:9

    Topics: Animals; Antineoplastic Agents; Apoptosis; Azetidines; Carcinoma, Squamous Cell; Cell Line, Tumor; Cellular Senescence; Humans; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Xenograft Model Antitumor Assays

2016
A combinatorial strategy for treating KRAS-mutant lung cancer.
    Nature, 2016, 06-30, Volume: 534, Issue:7609

    Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying combination targets for trametinib, a MEK inhibitor approved by the US Food and Drug Administration, which acts downstream of KRAS to suppress signalling through the mitogen-activated protein kinase (MAPK) cascade. Informed by a short-hairpin RNA screen, we show that trametinib provokes a compensatory response involving the fibroblast growth factor receptor 1 (FGFR1) that leads to signalling rebound and adaptive drug resistance. As a consequence, genetic or pharmacological inhibition of FGFR1 in combination with trametinib enhances tumour cell death in vitro and in vivo. This compensatory response shows distinct specificities: it is dominated by FGFR1 in KRAS-mutant lung and pancreatic cancer cells, but is not activated or involves other mechanisms in KRAS wild-type lung and KRAS-mutant colon cancer cells. Importantly, KRAS-mutant lung cancer cells and patients’ tumours treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations. These results demonstrate that FGFR1 can mediate adaptive resistance to trametinib and validate a combinatorial approach for treating KRAS-mutant lung cancer.

    Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Death; Cell Proliferation; Colonic Neoplasms; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Enzyme Activation; Feedback, Physiological; Female; Humans; Imidazoles; Lung Neoplasms; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Mutant Proteins; Mutation; Pancreatic Neoplasms; Phosphorylation; Proto-Oncogene Proteins p21(ras); Pyridazines; Pyridones; Pyrimidinones; Receptor, Fibroblast Growth Factor, Type 1; Xenograft Model Antitumor Assays

2016
Cardiogenic Shock and Respiratory Failure in a Patient With Metastatic Melanoma Receiving Trametinib Therapy.
    The oncologist, 2016, Volume: 21, Issue:9

    Topics: Humans; Melanoma; Pyridones; Pyrimidinones; Respiratory Insufficiency; Shock, Cardiogenic

2016
Rapid progression of intracranial melanoma metastases controlled with combined BRAF/MEK inhibition after discontinuation of therapy: a clinical challenge.
    Journal of neuro-oncology, 2016, Volume: 129, Issue:3

    Novel systemic therapies with anti-tumor activity in the brain including small molecules targeting BRAF and MEK, and immune checkpoint inhibition, offer the possibility of improved control of intracranial disease. A number of prospective trials support the judicious use of modern systemic therapies in patients with melanoma and limited brain metastases .The intracranial clinical course of patients who progress extracranially on BRAF/MEK inhibition remains poorly described in the literature. In this report, we highlight a series of clinical cases, with rapid progression of intracranial disease following discontinuation of dabrafenib/trametinib for extracranial disease progression or toxicity, a previously unreported finding in the medical literature with significant implications for patient care.

    Topics: Adult; Brain Neoplasms; Humans; Imidazoles; Magnetic Resonance Imaging; Male; MAP Kinase Kinase Kinases; Melanoma; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2016
ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma.
    Molecular cancer research : MCR, 2016, Volume: 14, Issue:10

    Recently, we identified that PREX1 overexpression is critical for metastatic but not tumorigenic growth in a mouse model of NRAS-driven melanoma. In addition, a PREX1 gene signature correlated with and was dependent on ERK MAPK activation in human melanoma cell lines. In the current study, the underlying mechanism of PREX1 overexpression in human melanoma was assessed. PREX1 protein levels were increased in melanoma tumor tissues and cell lines compared with benign nevi and normal melanocytes, respectively. Suppression of PREX1 by siRNA impaired invasion but not proliferation in vitro PREX1-dependent invasion was attributable to PREX1-mediated activation of the small GTPase RAC1 but not the related small GTPase CDC42. Pharmacologic inhibition of ERK signaling reduced PREX1 gene transcription and additionally regulated PREX1 protein stability. This ERK-dependent upregulation of PREX1 in melanoma, due to both increased gene transcription and protein stability, contrasts with the mechanisms identified in breast and prostate cancers, in which PREX1 overexpression was driven by gene amplification and HDAC-mediated gene transcription, respectively. Thus, although PREX1 expression is aberrantly upregulated and regulates RAC1 activity and invasion in these three different tumor types, the mechanisms of its upregulation are distinct and context dependent.. This study identifies an ERK-dependent mechanism that drives PREX1 upregulation and subsequent RAC1-dependent invasion in BRAF- and NRAS-mutant melanoma. Mol Cancer Res; 14(10); 1009-18. ©2016 AACR.

    Topics: Animals; Cell Line, Tumor; Cell Movement; Female; Gene Expression Regulation, Neoplastic; GTP Phosphohydrolases; Guanine Nucleotide Exchange Factors; Humans; Indazoles; Indoles; Male; MAP Kinase Signaling System; Melanoma; Membrane Proteins; Mice; Mutation; Piperazines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Up-Regulation; Vemurafenib

2016
Preclinical activity of EGFR and MEK1/2 inhibitors in the treatment of biliary tract carcinoma.
    Oncotarget, 2016, Aug-09, Volume: 7, Issue:32

    Biliary tract carcinomas (BTC) are malignant tumors with limited therapeutic options. Clinical experiences with anti-EGFR therapies have produced unsatisfactory results. The strategies of combined inhibition of EGFR and MEK1/2 could be a promising therapeutic option in BTC treatment. Preclinical activity of Panitumumab and Trametinib was tested in in vitro (EGI-1, MT-CHC01 and WITT cells) and in in vivo (xenograft) BTC models with different K-RAS mutational status. Trametinib reduced MAPK phosphorylation in wild type (WT) WITT cells and in both K-RAS mutated cells; in EGI-1 was also able to switch off EGFR activation. Panitumumab reduced the activation of its target only in EGI-1 cells, and of MAPK only in WITT cells. While Trametinib inhibited cell growth in K-RAS mutated cell lines, Panitumumab had no effect on proliferation independently by K-RAS status. The addition of Panitumumab to Trametinib did not significantly potentiate its anti-proliferative effect also in mutated cells. In vivo, Trametinib was able to significantly slow the tumor growth in K-RAS mutated xenograft models, but did not have effect on K-RAS WT cells; the addition of Panitumumab potentiated the Trametinib efficacy in MT-CHC01 and overcame the resistance to the anti-EGFR in WITT cells, in which the monotherapy was ineffective. Only in K-RAS mutated xenografts Trametinib alone or in combination with Panitumumab significantly decreased Ki67 positive cell fraction and CD31 angiogenesis markers. In conclusion, this preclinical study provides a rational to plan clinical trials assessing the efficacy of Trametinib in K-RAS mutated BTC patients and the combination with anti-EGFR in WT BTC patients.

    Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Biliary Tract Neoplasms; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Female; Humans; MAP Kinase Kinase Kinase 1; MAP Kinase Kinase Kinase 2; Mice; Mice, Inbred NOD; Mice, SCID; Panitumumab; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2016
Fatal gastrointestinal toxicity with ipilimumab after BRAF/MEK inhibitor combination in a melanoma patient achieving pathological complete response.
    Oncotarget, 2016, Aug-30, Volume: 7, Issue:35

    Approximately 50% of metastatic melanoma patients harbor BRAF mutations. Several treatment options including the combination of BRAF and MEK inhibitors (BRAF/MEKi) and immunotherapy (mainly anti CTLA-4 and anti PD-1 antibodies), have been shown to improve survival in these patients. Although preclinical data support the synergistic effect of both modalities in combination, data confirming the activity and tolerability of these combinations are not yet available in the clinical setting. Herein, we report the case of a melanoma patient treated with sequential BRAF/MEKi (dabrafenib plus trametinib) followed by the anti CTLA-4 antibody ipilimumab who achieved a pathological complete response. Unfortunately, the patient died due to fatal gastrointestinal (GI) toxicity. Analysis of the BRAFV600E mutation in circulating tumoral DNA (ctDNA) from peripheral blood samples and serial tumor tissue biopsies throughout treatment demonstrated a good correlation with clinical evolution.

    Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Neoplasms; DNA, Neoplasm; Fatal Outcome; Gastrointestinal Tract; Humans; Imidazoles; Ipilimumab; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Neoplastic Cells, Circulating; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2016
Combined therapy with dabrafenib and trametinib in BRAF-mutated metastatic melanoma in a real-life setting: the INT Milan experience.
    Tumori, 2016, Oct-13, Volume: 102, Issue:5

    Combination therapy with dabrafenib and trametinib is safer and more effective than BRAF inhibitor-based monotherapy for metastatic melanoma.. We retrospectively analyzed BRAF-mutated metastatic melanoma patients treated at our institution with daily oral dabrafenib 300 mg and trametinib 2 mg from November 2013 to April 2016. This clinical record included both untreated and previously treated stage IV melanomas. Physical examination and laboratory examinations were performed monthly and disease re-evaluations were performed every 3 months.. A total of 48 patients (24 male, 24 female) with BRAF-mutated metastatic melanoma received dabrafenib and trametinib; median age was 48 years (range 23-75). Median follow-up was 362.5 days (range 72-879). Best overall response rate consisted of 6.2% (3 patients) complete response, 64.6% (31) partial response, and 25% (12) stable disease; median time to best response was 11 weeks (range 5.7-125.5). Progression of disease was seen in 19 patients (39.6%), with median time to progression (TTP) of 26 weeks (range 8-54). A total of 15 patients (31.2%) died due to progression of disease. Median progression-free survival and median overall survival were not reached. To date, 30 patients (62.5%) are still under treatment. A total of 27 (56.2%) patients had at least one adverse event (AE); grade 3-4 AEs were seen in 4 cases (8.3%). The main toxicities were fever (25%), skin rash (14.6%), arthralgias (10.4%), and aspartate aminotransferase/alanine aminotransferase increase (8.3%). Treatment dose was reduced in 7 subjects (14.6%), with only one case of discontinuation due to AE.. Our data, using combined targeted therapy, are in line with the scientific literature in terms of both safety and effectiveness in a real-life setting.

    Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Follow-Up Studies; Humans; Imidazoles; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Neoplasm Metastasis; Neoplasm Staging; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Treatment Outcome; Young Adult

2016
Cutaneous wound healing through paradoxical MAPK activation by BRAF inhibitors.
    Nature communications, 2016, 08-01, Volume: 7

    BRAF inhibitors are highly effective therapies for the treatment of BRAF(V600)-mutated melanoma, with the main toxicity being a variety of hyperproliferative skin conditions due to paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyperproliferative skin changes improve when a MEK inhibitor is co-administered, as it blocks paradoxical MAPK activation. Here we show how the BRAF inhibitor vemurafenib accelerates skin wound healing by inducing the proliferation and migration of human keratinocytes through extracellular signal-regulated kinase (ERK) phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing mice models accelerates cutaneous wound healing through paradoxical MAPK activation; addition of a mitogen-activated protein kinase kinase (MEK) inhibitor reverses the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor does not increase the incidence of cutaneous squamous cell carcinomas in mice. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds.

    Topics: Administration, Topical; Animals; Carcinogenesis; Carcinogens; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Female; Humans; Incidence; Indoles; Keratinocytes; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Neoplasms, Experimental; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin; Skin Neoplasms; Sulfonamides; Treatment Outcome; Vemurafenib; Wound Healing

2016
Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer.
    Cell reports, 2016, 08-16, Volume: 16, Issue:7

    Pancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors exhibit no clearly defined therapeutic target. High-throughput drug screens using patient-derived cell lines found rare examples of sensitivity to monotherapy, with most models requiring combination therapy. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses. Out of more than 500 single and combination drug regimens tested, no single treatment was effective for the majority of PDAC tumors, and each case had unique sensitivity profiles that could not be predicted using genetic analyses. These data indicate a shortcoming of reliance on genetic analysis to predict efficacy of currently available agents against PDAC and suggest that sensitivity profiling of patient-derived models could inform personalized therapy design for PDAC.

    Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Dasatinib; Docetaxel; Drug Resistance, Neoplasm; Everolimus; Exome; Humans; Mice; Models, Genetic; Models, Statistical; Pancreatic Neoplasms; Precision Medicine; Prognosis; Pyridones; Pyrimidinones; Taxoids; Xenograft Model Antitumor Assays

2016
miR-579-3p controls melanoma progression and resistance to target therapy.
    Proceedings of the National Academy of Sciences of the United States of America, 2016, 08-23, Volume: 113, Issue:34

    Therapy of melanoma patients harboring activating mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) oncogene with a combination of BRAF and MEK inhibitors is plagued by the development of drug resistance. Mutational events, as well as adaptive mechanisms, contribute to the development of drug resistance. In this context we uncover here the role of a miRNA, miR-579-3p. We first show that low expression of miR-579-3p is a negative prognostic factor correlating with poor survival. Expression levels of miR-579-3p decrease from nevi to stage III/IV melanoma samples and even further in cell lines resistant to BRAF/MEK inhibitors. Mechanistically, we demonstrate that miR-579-3p acts as an oncosuppressor by targeting the 3'UTR of two oncoproteins: BRAF and an E3 ubiquitin protein ligase, MDM2. Moreover miR-579-3p ectopic expression impairs the establishment of drug resistance in human melanoma cells. Finally, miR-579-3p is strongly down-regulated in matched tumor samples from patients before and after the development of resistance to targeted therapies.

    Topics: 3' Untranslated Regions; Antineoplastic Agents; Base Sequence; Binding Sites; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Indoles; Melanoma; MicroRNAs; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-mdm2; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Survival Analysis; Vemurafenib

2016
Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling.
    Nature, 2016, 09-01, Volume: 537, Issue:7618

    Deregulation of the Ras-mitogen activated protein kinase (MAPK) pathway is an early event in many different cancers and a key driver of resistance to targeted therapies. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes. Kinase suppressor of Ras (KSR) is a MAPK scaffold that is subject to allosteric regulation through dimerization with RAF. Direct targeting of KSR could have important therapeutic implications for cancer; however, testing this hypothesis has been difficult owing to a lack of small-molecule antagonists of KSR function. Guided by KSR mutations that selectively suppress oncogenic, but not wild-type, Ras signalling, we developed a class of compounds that stabilize a previously unrecognized inactive state of KSR. These compounds, exemplified by APS-2-79, modulate KSR-dependent MAPK signalling by antagonizing RAF heterodimerization as well as the conformational changes required for phosphorylation and activation of KSR-bound MEK (mitogen-activated protein kinase kinase). Furthermore, APS-2-79 increased the potency of several MEK inhibitors specifically within Ras-mutant cell lines by antagonizing release of negative feedback signalling, demonstrating the potential of targeting KSR to improve the efficacy of current MAPK inhibitors. These results reveal conformational switching in KSR as a druggable regulator of oncogenic Ras, and further suggest co-targeting of enzymatic and scaffolding activities within Ras-MAPK signalling complexes as a therapeutic strategy for overcoming Ras-driven cancers.

    Topics: Alleles; Allosteric Regulation; Cell Line; Enzyme Stability; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Models, Molecular; Mutation; Neoplasms; Oncogenes; Phosphorylation; Protein Binding; Protein Conformation; Protein Multimerization; Protein Serine-Threonine Kinases; Pyridones; Pyrimidinones; Quinazolines; raf Kinases; ras Proteins

2016
Upfront targeted therapy for symptomatic melanoma brain metastases: paradigm changing?
    CNS oncology, 2016, Volume: 5, Issue:4

    The standard management of a single brain metastasis is usually maximal resection when feasible followed by radiotherapy. In case of multiple lesions, several options have to be considered depending on the natural behavior of the primary tumor, the localization of brain lesions, their functional impact and related symptoms. In case of life-threatening brain metastasis, debulking surgery is often proposed first, with the risk of major bleeding and postponing the initiation of other treatments. This approach is now challenged by the rapid tumor shrinkage that could be observed with novel targeted therapies. Here we report the case of a patient suffering from a melanoma with multiple brain metastasis, treated with BRAF and MEK double blockade, with impressive and rapid response.

    Topics: Brain; Brain Neoplasms; Humans; Imidazoles; Lymph Node Excision; Lymph Nodes; Magnetic Resonance Imaging; Melanoma; Middle Aged; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2016
Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer.
    Oncotarget, 2016, Dec-13, Volume: 7, Issue:50

    KRAS mutations are an established predictor of lack of response to EGFR-targeted therapies in patients with metastatic colorectal cancer (mCRC). However, little is known about the role of the rarer NRAS mutations as a mechanism of primary resistance to the anti-EGFR monoclonal antibody cetuximab in wild-type KRAS mCRC. Using isogenic mCRC cells with a heterozygous knock-in of the NRAS activating mutation Q61K, we aimed to elucidate the mechanism(s) by which mutant NRAS blocks cetuximab from inhibiting mCRC growth. NRASQ61K/+ cells were refractory to cetuximab-induced growth inhibition. Pathway-oriented proteome profiling revealed that cetuximab-unresponsive ERK1/2 phosphorylation was the sole biomarker distinguishing cetuximab-refractory NRASQ61K/+ from cetuximab-sensitive NRAS+/+ cells. We therefore employed four representative MEK1/2 inhibitors (binimetinib, trametinib, selumetinib, and pimasertib) to evaluate the therapeutic value of MEK/ERK signaling in cetuximab-refractory NRAS mutation-induced mCRC. Co-treatment with an ineffective dose of cetuximab augmented, up to more than 1,300-fold, the cytotoxic effects of pimasertib against NRASQ61K/+ cells. Simultaneous combination of MEK1/2 inhibitors with cetuximab resulted in extremely high and dose-dependent synthetic lethal effects, which were executed, at least in part, by exacerbated apoptotic cell death. Dynamic monitoring of real-time cell growth rates confirmed that cetuximab synergistically sensitized NRASQ61K/+ cellsto MEK1/2 inhibition. Our discovery of a synthetic lethal interaction of cetuximab in combination with MEK1/2 inhibition for the NRAS mutant subgroup of mCRC underscores the importance of therapeutic intervention both in the MEK-ERK and EGFR pathways to achieve maximal therapeutic efficacy against NRAS-mutant mCRC tumors.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Cetuximab; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; GTP Phosphohydrolases; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Membrane Proteins; Mutation; Niacinamide; Phosphorylation; Protein Kinase Inhibitors; Proteomics; Pyridones; Pyrimidinones; Signal Transduction; Transfection

2016
Epidermotropic progression of melanoma during therapy with vemurafenib and trametinib.
    Journal of the American Academy of Dermatology, 2016, Volume: 75, Issue:4

    Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dermoscopy; Disease Progression; Drug Substitution; Epidermis; Fibrosis; Humans; Imidazoles; Indoles; Male; Melanoma; Melanoma, Cutaneous Malignant; Melanosis; Mutation, Missense; Neoplasm Proteins; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Remission Induction; Skin Neoplasms; Substrate Specificity; Sulfonamides; Vemurafenib

2016
MEK inhibitors as a novel therapy for neuroblastoma: Their in vitro effects and predicting their efficacy.
    Journal of pediatric surgery, 2016, Volume: 51, Issue:12

    A recent study reported that relapsed neuroblastomas had frequent RAS-ERK pathway mutations. We herein investigated the effects and pathways of MEK inhibitors, which inhibit the RAS-ERK pathway, as a new molecular-targeted therapy for refractory neuroblastomas.. Five neuroblastoma cell lines were treated with trametinib (MEK inhibitor) or CH5126766 (RAF/MEK inhibitor). Growth inhibition was analyzed using a cell viability assay. ERK phosphorylation and the MYCN expression were analyzed by immunoblotting or immunohistochemistry. RAS/RAF mutations were identified by direct sequencing or through the COSMIC database.. Both MEK inhibitors showed growth inhibition effects on cells with ERK phosphorylation, but almost no effect on cells without. In immunoblotting analyses, ERK phosphorylation and MYCN expression were suppressed in ERK active cells by these drugs. Furthermore, phosphorylated-ERK immunohistochemistry corresponded to the drug responses. Regarding the relationship between RAS/Raf mutations and ERK phosphorylation, ERK was phosphorylated in one cell line (NLF) without RAS/Raf mutations.. MEK inhibitors are a promising molecular-targeted therapeutic option for ERK active neuroblastomas. The efficacy of MEK inhibitors corresponds to ERK phosphorylation, while RAS/RAF mutations are not always detected in drug-sensitive cells. Phosphorylated-ERK immunohistochemistry is thus a useful method to analyze ERK activity and predict the therapeutic effects of MEK inhibitors.

    Topics: Cell Line, Tumor; Coumarins; Humans; MAP Kinase Signaling System; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Neuroblastoma; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction

2016
Vemurafenib-resistant BRAF-V600E-mutated melanoma is regressed by MEK-targeting drug trametinib, but not cobimetinib in a patient-derived orthotopic xenograft (PDOX) mouse model.
    Oncotarget, 2016, Nov-01, Volume: 7, Issue:44

    Melanoma is a recalcitrant disease. The present study used a patient-derived orthotopic xenograft (PDOX) model of melanoma to test sensitivity to three molecularly-targeted drugs and one standard chemotherapeutic. A BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a PDOX model. Two weeks after implantation, 50 PDOX nude mice were divided into 5 groups: G1, control without treatment; G2, vemurafenib (VEM) (30 mg/kg); G3; temozolomide (TEM) (25 mg/kg); G4, trametinib (TRA) (0.3 mg/kg); and G5, cobimetinib (COB) (5 mg/kg). Each drug was administered orally, daily for 14 consecutive days. Tumor sizes were measured with calipers twice a week. On day 14 from initiation of treatment, TRA, an MEK inhibitor, was the only agent of the 4 tested that caused tumor regression (P < 0.001 at day 14). In contrast, another MEK inhibitor, COB, could slow but not arrest growth or cause regression of the melanoma. First-line therapy TEM could slow but not arrest tumor growth or cause regression. The patient in this study had a BRAF-V600E-mutant melanoma and would be considered to be a strong candidate for VEM as first-line therapy, since VEM targets this mutation. However, VEM was not effective. The PDOX model thus helped identify the very-high efficacy of TRA against the melanoma PDOX and is a promising drug for this patient. These results demonstrate the powerful precision of the PDOX model for cancer therapy, not achievable by genomic analysis alone.

    Topics: Aged; Animals; Antineoplastic Agents; Azetidines; Drug Resistance, Neoplasm; Female; Humans; Indoles; Melanoma; Mice; Mitogen-Activated Protein Kinase Kinases; Mutation; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib; Xenograft Model Antitumor Assays

2016
The MEK inhibitor trametinib separates murine graft-versus-host disease from graft-versus-tumor effects.
    JCI insight, 2016, 07-07, Volume: 1, Issue:10

    The efficacy of allogeneic hematopoietic stem cell transplantation for hematologic malignancies is limited by the difficulty in suppressing graft-versus-host disease (GVHD) without compromising graft-versus-tumor (GVT) effects. We previously showed that RAS/MEK/ERK signaling depends on memory differentiation in human T cells, which confers susceptibility to selective inhibition of naive T cells. Actually, antineoplastic MEK inhibitors selectively suppress alloreactive T cells, sparing virus-specific T cells in vitro. Here, we show that trametinib, a MEK inhibitor clinically approved for melanoma, suppresses GVHD safely without affecting GVT effects in vivo. Trametinib prolonged survival of GVHD mice and attenuated GVHD symptoms and pathology in the gut and skin. It inhibited ERK1/2 phosphorylation and expansion of donor T cells, sparing Tregs and B cells. Although high-dose trametinib inhibited myeloid cell engraftment, low-dose trametinib suppressed GVHD without severe adverse events. Notably, trametinib facilitated the survival of mice transplanted with allogeneic T cells and P815 tumor cells with no residual P815 cells observed in the livers and spleens, whereas tacrolimus resulted in P815 expansion. These results confirm that trametinib selectively suppresses GVHD-inducing T cells while sparing antitumor T cells in vivo, which makes it a promising candidate for translational studies aimed at preventing or treating GVHD.

    Topics: Animals; Graft vs Host Disease; Graft vs Tumor Effect; Hematopoietic Stem Cell Transplantation; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2016
The future of melanoma therapy: developing new drugs and improving the use of old ones.
    Future oncology (London, England), 2016, Volume: 12, Issue:22

    Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Azetidines; Chemotherapy, Adjuvant; Drug Discovery; Drug Therapy, Combination; Humans; Imidazoles; Indoles; Ipilimumab; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Molecular Targeted Therapy; Neoplasm Metastasis; Nivolumab; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

2016
Growth arrest by activated BRAF and MEK inhibition in human anaplastic thyroid cancer cells.
    International journal of oncology, 2016, Volume: 49, Issue:6

    Anaplastic thyroid cancer (ATC) is a rare malignancy that progresses extremely aggressively and often results in dismal prognosis. We investigated the efficacy of inhibiting the activated RAS/RAF/MEK pathway in ATC cells aiming to clarify the mechanism of effect and resistance. Four human ATC cell lines (ACT-1, OCUT-2, OCUT-4 and OCUT-6) were used. OCUT-4 had a BRAF mutation. OCUT-2 had both BRAF and PI3KCA mutations. ACT-1 and OCUT-6 had wild-type BRAF and NRAS mutations. The effects of dabrafenib, a selective inhibitor of the BRAFV600E kinase, and trametinib, a reversible inhibitor of MEK activity, were investigated. Dabrafenib strongly inhibited the viability in BRAF mutated cells by demonstrating G0/G1-arrest via the downregulation of MEK/ERK phosphorylation. Upregulated phosphorylation of MEK was observed in RAS mutated cells after dabrafenib treatment and caused VEGF upregulation, but was not related to the cellular proliferation. Trametinib inhibited the cellular viability to variable degrees in every cell by downregulating ERK phosphorylation. Dual blockade by both inhibitors demonstrated clear cytostatic effect in all the cells. OCUT-4 showed the weakest sensitivity to trametinib, no additional effect of either inhibitor in combination with the other, and an increase of SNAI1 mRNA expression after treatment with inhibitors, suggesting a mechanism for resistance. Our findings demonstrated the efficacy of a mutation-selective BRAF inhibitor and a MEK inhibitor in human ATC cells in a genetic alteration-specific manner.

    Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; G1 Phase Cell Cycle Checkpoints; GTP Phosphohydrolases; Humans; Imidazoles; MAP Kinase Kinase 1; Membrane Proteins; Nuclear Proteins; Oximes; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; RNA, Messenger; Snail Family Transcription Factors; Thyroid Carcinoma, Anaplastic; Transcription Factors; Vascular Endothelial Growth Factor A

2016
MEK inhibitors against MET-amplified non-small cell lung cancer.
    International journal of oncology, 2016, Volume: 49, Issue:6

    Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.

    Topics: A549 Cells; Antineoplastic Agents; Benzamides; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crizotinib; Diphenylamine; ErbB Receptors; Humans; Lung Neoplasms; MAP Kinase Kinase 1; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyridones; Pyrimidinones

2016
Triple Therapy Improves Colorectal Cancer Response.
    Cancer discovery, 2016, Volume: 6, Issue:12

    Findings from a phase I/II study indicate a higher response rate among patients with BRAF-mutant metastatic colorectal cancer treated with an EGFR inhibitor alongside dual, as opposed to single-level, MAPK blockade. Panitumumab combined with trametinib and dabrafenib only modestly increased median progression-free survival, however; a short-lived decrease in responders' BRAF V600E mutant allele fraction and the emergence of RAS mutations may have been contributing factors.

    Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Humans; Imidazoles; MAP Kinase Signaling System; Mutation; Oximes; Panitumumab; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

2016
Improving nelarabine efficacy in T cell acute lymphoblastic leukemia by targeting aberrant PI3K/AKT/mTOR signaling pathway.
    Journal of hematology & oncology, 2016, 10-24, Volume: 9, Issue:1

    Although in recent years, the introduction of novel chemotherapy protocols has improved the outcome of T cell acute lymphoblastic leukemia (T-ALL) patients, refractory and/or relapsing disease remains a foremost concern. In this context, a major contribution was provided by the introduction of the nucleoside analog nelarabine, approved for salvage treatment of T-ALL patients with refractory/relapsed disease. However, nelarabine could induce a life-threatening, dose-dependent neurotoxicity. To improve nelarabine efficacy, we have analyzed its molecular targets, testing selective inhibitors of such targets in combination with nelarabine.. The effectiveness of nelarabine as single agent or in combination with PI3K, Bcl2, and MEK inhibitors was evaluated on human T-ALL cell lines and primary T-ALL refractory/relapsed lymphoblasts. The efficacy of signal modulators in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed by flow cytometry, western blotting, and quantitative real-time PCR in T-ALL settings.. Treatment with nelarabine as a single agent identified two groups of T-ALL cell lines, one sensitive and one resistant to the drug. Whereas sensitive T-ALL cells showed a significant increase of apoptosis and a strong down-modulation of PI3K signaling, resistant T-ALL cells showed a hyperactivation of AKT and MEK/ERK1/2 signaling pathways, not caused by differences in the expression of nelarabine transporters or metabolic activators. We then studied the combination of nelarabine with the PI3K inhibitors (both pan and dual γ/δ inhibitors), with the Bcl2 specific inhibitor ABT199, and with the MEK inhibitor trametinib on both T-ALL cell lines and patient samples at relapse, which displayed constitutive activation of PI3K signaling and resistance to nelarabine alone. The combination with the pan PI3K inhibitor ZSTK-474 was the most effective in inhibiting the growth of T-ALL cells and was synergistic in decreasing cell survival and inducing apoptosis in nelarabine-resistant T-ALL cells. The drug combination caused AKT dephosphorylation and a downregulation of Bcl2, while nelarabine alone induced an increase in p-AKT and Bcl2 signaling in the resistant T-ALL cells and relapsed patient samples.. These findings indicate that nelarabine in combination with PI3K inhibitors may be a promising therapeutic strategy for the treatment of T-ALL relapsed patients.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arabinonucleosides; Bridged Bicyclo Compounds, Heterocyclic; Cell Survival; Drug Synergism; Humans; Phosphoinositide-3 Kinase Inhibitors; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Signal Transduction; Sulfonamides; TOR Serine-Threonine Kinases; Triazines; Tumor Cells, Cultured

2016
RSK1 protects P-glycoprotein/ABCB1 against ubiquitin-proteasomal degradation by downregulating the ubiquitin-conjugating enzyme E2 R1.
    Scientific reports, 2016, 10-27, Volume: 6

    Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bortezomib; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; F-Box Proteins; HEK293 Cells; Humans; Mitogen-Activated Protein Kinase 3; Phosphorylation; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Binding; Pyridones; Pyrimidinones; Ribosomal Protein S6 Kinases, 90-kDa; RNA Interference; Ubiquitin; Ubiquitin-Conjugating Enzymes

2016
Phosphoproteome Profiling Reveals Molecular Mechanisms of Growth-Factor-Mediated Kinase Inhibitor Resistance in EGFR-Overexpressing Cancer Cells.
    Journal of proteome research, 2016, 12-02, Volume: 15, Issue:12

    Although substantial progress has been made regarding the use of molecularly targeted cancer therapies, resistance almost invariably develops and presents a major clinical challenge. The tumor microenvironment can rescue cancer cells from kinase inhibitors by growth-factor-mediated induction of pro-survival pathways. Here we show that epidermal growth factor receptor (EGFR) inhibition by Gefitinib is counteracted by growth factors, notably FGF2, and we assessed the global molecular consequences of this resistance at the proteome and phosphoproteome level in A431 cells. Tandem mass tag peptide labeling and quantitative mass spectrometry allowed the identification and quantification of 22 000 phosphopeptides and 8800 proteins in biological triplicates without missing values. The data show that FGF2 protects the cells from the antiproliferative effect of Gefitinib and largely prevents reprogramming of the proteome and phosphoproteome. Simultaneous EGFR/FGFR or EGFR/GSG2 (Haspin) inhibition overcomes this resistance, and the phosphoproteomic experiments further prioritized the RAS/MEK/ERK as well as the PI3K/mTOR axis for combination treatment. Consequently, the MEK inhibitor Trametinib prevented FGF2-mediated survival of EGFR inhibitor-resistant cells when used in combination with Gefitinib. Surprisingly, the PI3K/mTOR inhibitor Omipalisib reversed resistance mediated by all four growth factors tested, making it an interesting candidate for mitigating the effects of the tumor microenvironment.

    Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Fibroblast Growth Factor 2; Gefitinib; Humans; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Phosphopeptides; Protein Kinase Inhibitors; Proteome; Proteomics; Pyridones; Pyrimidinones; Quinazolines

2016
Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis.
    Cancer research, 2016, 11-01, Volume: 76, Issue:21

    Targeted therapies elicit seemingly paradoxical and poorly understood effects on tumor immunity. Here, we show that the MEK inhibitor trametinib abrogates cytokine-driven expansion of monocytic myeloid-derived suppressor cells (mMDSC) from human or mouse myeloid progenitors. MEK inhibition also reduced the production of the mMDSC chemotactic factor osteopontin by tumor cells. Together, these effects reduced mMDSC accumulation in tumor-bearing hosts, limiting the outgrowth of KRas-driven breast tumors, even though trametinib largely failed to directly inhibit tumor cell proliferation. Accordingly, trametinib impeded tumor progression in vivo through a mechanism requiring CD8

    Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Female; Humans; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mutation; Myeloid Cells; Myelopoiesis; Neoplasms; Osteopontin; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; T-Lymphocytes

2016
Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials.
    The Lancet. Oncology, 2016, Volume: 17, Issue:12

    Dabrafenib plus trametinib treatment provides significant benefits over BRAF-inhibitor monotherapy in patients with BRAF. We did a retrospective individual data analysis based on all published randomised trials that included treatment-naive patients with BRAF. 617 patients were included in this analysis with a median follow-up of 20·0 months (range 0-48·0, IQR 10·1-24·8); 396 patients had progression events (ie, disease progression or death) and 290 patients had died. Median progression-free survival (11·1 months [95% CI 9·7-12·9]), median overall survival (25·6 months [23·1-34·3]), 1-year progression-free survival (48% [44-52]) and overall survival (74% [71-78]), and 2-year progression-free survival (30% [26-34]) and overall survival (53% [49-57]) were consistent with those in the individual trials. Patients with normal lactate dehydrogenase (LDH) concentration and fewer than three organ sites containing metastases (n=237) had the longest 1-year progression-free survival (68% [95% CI 62-74]) and overall survival (90% [87-94]) and 2-year progression-free survival (46% [40-54]) and overall survival (75% [70-81]), whereas patients with LDH concentration at least two times the upper limit of normal (n=70) had the shortest 1-year progression-free survival (8% [3-19]) and overall survival (40% [29-55]) and 2-year progression-free survival (2% [0-13]) and overall survival (7% [3-19]). Of patients with disease progression (n=379), survival after progression was longest in those with progression in baseline or new non-CNS lesions (n=205; median 10·0 months [95% CI 7·9-12·0]) and shortest in those with new CNS lesions or concurrent progression in baseline and new lesions (n=171; median 4·0 months [3·5-4·9]).. Several patient and clinical characteristics at and after baseline are associated with outcomes with dabrafenib plus trametinib, and durable benefit is possible with targeted treatment in defined patient subsets.. Novartis.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Humans; Imidazoles; Male; Melanoma; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Randomized Controlled Trials as Topic; Retrospective Studies

2016
Optimizing combination dabrafenib and trametinib therapy in BRAF mutation-positive advanced melanoma patients: Guidelines from Australian melanoma medical oncologists.
    Asia-Pacific journal of clinical oncology, 2016, Volume: 12 Suppl 7

    BRAF mutations occur commonly in metastatic melanomas and inhibition of mutant BRAF and the downstream kinase MEK results in rapid tumor regression and prolonged survival in patients. Combined therapy with BRAF and MEK inhibition improves response rate, progression free survival and overall survival compared with single agent BRAF inhibition, and reduces the skin toxicity that is seen with BRAF inhibitor monotherapy. However, this combination is associated with an increase in other toxicities, particularly drug-related pyrexia, which affects approximately 50% of patients treated with dabrafenib and trametinib (CombiDT). We provide guidance on managing adverse events likely to arise during treatment with combination BRAF and MEK inhibition with CombiDT: pyrexia, skin conditions, fatigue; and discuss management of CombiDT during surgery and radiotherapy. By improving tolerability and in particular preventing unnecessary treatment cessations or reduction in drug exposure, best outcomes can be achieved for patients undergoing CombiDT therapy.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Australia; Drug Eruptions; Exanthema; Fever; Humans; Imidazoles; MAP Kinase Kinase Kinases; Medical Oncology; Melanoma; Melanoma, Cutaneous Malignant; Mutation; Oximes; Practice Guidelines as Topic; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2016
Activation of mutant TERT promoter by RAS-ERK signaling is a key step in malignant progression of BRAF-mutant human melanomas.
    Proceedings of the National Academy of Sciences of the United States of America, 2016, 12-13, Volume: 113, Issue:50

    Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters. Our study provides evidence that the mutant TERT promoter is a key substrate downstream of the RAS-ERK pathway. Reactivating TERT and hence reconstituting telomerase is an important step in melanoma progression from nonmalignant nevi with BRAF mutations. Hence, combined targeting of RAS-ERK and TERT promoter remodeling is a promising avenue to limit long-term survival of a majority of melanomas that harbor these two mutations.

    Topics: Cell Line, Tumor; Disease Progression; Humans; Imidazoles; MAP Kinase Signaling System; Melanoma; Models, Biological; Mutation; Oximes; Promoter Regions, Genetic; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; ras Proteins; RNA Polymerase II; Skin Neoplasms; Telomerase

2016
MEK inhibitors block growth of lung tumours with mutations in ataxia-telangiectasia mutated.
    Nature communications, 2016, 12-06, Volume: 7

    Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours.

    Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Benzamides; Cell Line, Tumor; Cell Proliferation; Diphenylamine; Humans; Lung Neoplasms; Mice, Nude; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; ras Proteins; RNA Interference; Thiophenes; Urea; Xenograft Model Antitumor Assays

2016
Facing the challenges of new melanoma-targeted therapies: Treatment of severe fevers associated with dabrafenib/trametinib combination therapy.
    Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners, 2015, Volume: 21, Issue:4

    With the emergence of new oral therapies for metastatic melanoma to the market, as well as ongoing pre-marketing trials and special access schemes, it is important to keep up to date with the side effect profiles of these medications. A common side effect associated with the BRAF inhibitor dabrafenib is severe fever symptoms such as pyrexia and rigors/chills; however, treatment options are limited. We report a patient who was debilitated by severe pyrexia and rigors caused by dabrafenib used in combination with trametinib to treat metastatic melanoma, who was treated with low-dose steroids. To our knowledge, the use of prednisolone for the treatment and prevention of further dabrafenib-associated pyrexia is not published; however, it is a low risk and low cost option that was very effective in this case.

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cefepime; Cephalosporins; Drug Delivery Systems; Female; Fever; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Severity of Illness Index

2015
New RAS-mutant pancreatic adenocarcinoma with combined BRAF and MEK inhibition for metastatic melanoma.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015, Apr-10, Volume: 33, Issue:11

    Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biopsy; DNA Mutational Analysis; Humans; Imidazoles; Immunohistochemistry; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Oximes; Pancreatic Neoplasms; Positron-Emission Tomography; Predictive Value of Tests; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; ras Proteins; Risk Factors; Skin Neoplasms; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

2015
Combined MEK inhibition and BMP2 treatment promotes osteoblast differentiation and bone healing in Nf1Osx -/- mice.
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2015, Volume: 30, Issue:1

    Neurofibromatosis type I (NF1) is an autosomal dominant disease with an incidence of 1/3000, caused by mutations in the NF1 gene, which encodes the RAS/GTPase-activating protein neurofibromin. Non-bone union after fracture (pseudarthrosis) in children with NF1 remains a challenging orthopedic condition to treat. Recent progress in understanding the biology of neurofibromin suggested that NF1 pseudarthrosis stems primarily from defects in the bone mesenchymal lineage and hypersensitivity of hematopoietic cells to TGFβ. However, clinically relevant pharmacological approaches to augment bone union in these patients remain limited. In this study, we report the generation of a novel conditional mutant mouse line used to model NF1 pseudoarthrosis, in which Nf1 can be ablated in an inducible fashion in osteoprogenitors of postnatal mice, thus circumventing the dwarfism associated with previous mouse models where Nf1 is ablated in embryonic mesenchymal cell lineages. An ex vivo-based cell culture approach based on the use of Nf1(flox/flox) bone marrow stromal cells showed that loss of Nf1 impairs osteoprogenitor cell differentiation in a cell-autonomous manner, independent of developmental growth plate-derived or paracrine/hormonal influences. In addition, in vitro gene expression and differentiation assays indicated that chronic ERK activation in Nf1-deficient osteoprogenitors blunts the pro-osteogenic property of BMP2, based on the observation that only combination treatment with BMP2 and MEK inhibition promoted the differentiation of Nf1-deficient osteoprogenitors. The in vivo preclinical relevance of these findings was confirmed by the improved bone healing and callus strength observed in Nf1osx (-/-) mice receiving Trametinib (a MEK inhibitor) and BMP2 released locally at the fracture site via a novel nanoparticle and polyglycidol-based delivery method. Collectively, these results provide novel evidence for a cell-autonomous role of neurofibromin in osteoprogenitor cells and insights about a novel targeted approach for the treatment of NF1 pseudoarthrosis.

    Topics: Animals; Bone Morphogenetic Protein 2; Bone Regeneration; Cell Differentiation; Disease Models, Animal; Drug Delivery Systems; Humans; MAP Kinase Kinase Kinases; Mesenchymal Stem Cells; Mice; Mice, Knockout; Nanoparticles; Neurofibromatosis 1; Neurofibromin 1; Protein Kinase Inhibitors; Pseudarthrosis; Pyridones; Pyrimidinones

2015
Effects of MEK inhibitors GSK1120212 and PD0325901 in vivo using 10-plex quantitative proteomics and phosphoproteomics.
    Proteomics, 2015, Volume: 15, Issue:2-3

    Multiplexed isobaric tag based quantitative proteomics and phosphoproteomics strategies can comprehensively analyze drug treatments effects on biological systems. Given the role of mitogen-activated protein/extracellular signal-regulated kinase (MEK) signaling in cancer and mitogen-activated protein kinase (MAPK)-dependent diseases, we sought to determine if this pathway could be inhibited safely by examining the downstream molecular consequences. We used a series of tandem mass tag 10-plex experiments to analyze the effect of two MEK inhibitors (GSK1120212 and PD0325901) on three tissues (kidney, liver, and pancreas) from nine mice. We quantified ∼ 6000 proteins in each tissue, but significant protein-level alterations were minimal with inhibitor treatment. Of particular interest was kidney tissue, as edema is an adverse effect of these inhibitors. From kidney tissue, we enriched phosphopeptides using titanium dioxide (TiO2 ) and quantified 10 562 phosphorylation events. Further analysis by phosphotyrosine peptide immunoprecipitation quantified an additional 592 phosphorylation events. Phosphorylation motif analysis revealed that the inhibitors decreased phosphorylation levels of proline-x-serine-proline (PxSP) and serine-proline (SP) sites, consistent with extracellular-signal-regulated kinase (ERK) inhibition. The MEK inhibitors had the greatest decrease on the phosphorylation of two proteins, Barttin and Slc12a3, which have roles in ion transport and fluid balance. Further studies will provide insight into the effect of these MEK inhibitors with respect to edema and other adverse events in mouse models and human patients.

    Topics: Amino Acid Sequence; Animals; Benzamides; Diphenylamine; Humans; Kidney; Liver; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Molecular Sequence Data; Pancreas; Phosphopeptides; Phosphorylation; Protein Kinase Inhibitors; Proteome; Proteomics; Pyridones; Pyrimidinones; Tandem Mass Spectrometry

2015
BRAF/NRAS wild-type melanoma, NF1 status and sensitivity to trametinib.
    Pigment cell & melanoma research, 2015, Volume: 28, Issue:1

    Topics: Cell Line, Tumor; DNA Mutational Analysis; Drug Screening Assays, Antitumor; GTP Phosphohydrolases; Humans; Melanoma; Membrane Proteins; Mutation; Neurofibromin 1; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2015
Response to MAPK pathway inhibitors in BRAF V600M-mutated metastatic melanoma.
    Journal of clinical pharmacy and therapeutics, 2015, Volume: 40, Issue:1

    The management of metastatic melanoma has changed significantly in the past decade with the development of immunotherapies and targeted molecular therapies. Trials of targeted therapies have focused mainly on patients with the most common BRAF V600 mutations, namely V600E/K substitutions, with very little information available on the benefit of targeted therapies on less commonly occurring mutations such as V600R/D and M.. We present a 54-year-old man with metastatic melanoma harbouring a rare BRAF V600M mutation, who experienced clinical and radiological response to combined therapy with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib.. As our understanding of these therapies evolves and an increasing number of patients have mutational testing performed, there is a clear imperative--as highlighted by this case--to test for rarer mutations and facilitate their inclusion both in everyday practice and in future clinical trials.

    Topics: Abdominal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Humans; Imidazoles; Intestinal Neoplasms; Lymphatic Metastasis; Male; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2015
BRAF and MEK inhibition variably affect GD2-specific chimeric antigen receptor (CAR) T-cell function in vitro.
    Journal of immunotherapy (Hagerstown, Md. : 1997), 2015, Volume: 38, Issue:1

    Cancer immunotherapy has long been used in the treatment of metastatic melanoma, and an anti-CTLA-4 monoclonal antibody treatment has recently been approved by the US Food and Drug Administration. Targeted therapies such as small molecule kinase inhibitors targeting deregulated mitogen-activated protein kinase (MAPK) signaling have markedly improved melanoma control in up to 50% of metastatic disease patients and have likewise been recently approved. Combination therapies for melanoma have been proposed as a way to exploit the high-level but short-term responses associated with kinase inhibitor therapies and the low-level but longer-term responses associated with immunotherapy. Cancer immunotherapy now includes adoptive transfer of autologous tumor-specific chimeric antigen receptor (CAR) T cells and this mode of therapy is a candidate for combination with small molecule drugs. This paper describes CART cells that target GD2-expressing melanoma cells and investigates the effects of approved MAPK pathway-targeted therapies for melanoma [vemurafenib (Vem), dabrafenib (Dab), and trametinib (Tram)] on the viability, activation, proliferation, and cytotoxic T lymphocyte activity of these CAR T cells, as well as on normal peripheral blood mononuclear cells. We report that, although all these drugs lead to inhibition of stimulated T cells at high concentrations in vitro, only Vem inhibited T cells at concentrations equivalent to reported plasma concentrations in treated patients. Although the combination of Dab and Tram also resulted in inhibition of T-cell effector functions at some therapeutic concentrations, Dab itself had little adverse effect on CAR T-cell function. These findings may have implications for novel therapeutic combinations of adoptive CAR T-cell immunotherapy and MAPK pathway inhibitors.

    Topics: Antineoplastic Agents; Cell Line; Cell Survival; Flow Cytometry; Humans; Imidazoles; Immunotherapy; In Vitro Techniques; Indoles; Leukocytes, Mononuclear; Lymphocyte Activation; MAP Kinase Signaling System; Melanoma; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Receptors, Antigen, T-Cell; Sulfonamides; T-Lymphocytes, Cytotoxic; Transfection; Vemurafenib

2015
A stress-induced early innate response causes multidrug tolerance in melanoma.
    Oncogene, 2015, Aug-20, Volume: 34, Issue:34

    Acquired drug resistance constitutes a major challenge for effective cancer therapies with melanoma being no exception. The dynamics leading to permanent resistance are poorly understood but are important to design better treatments. Here we show that drug exposure, hypoxia or nutrient starvation leads to an early innate cell response in melanoma cells resulting in multidrug resistance, termed induced drug-tolerant cells (IDTCs). Transition into the IDTC state seems to be an inherent stress reaction for survival toward unfavorable environmental conditions or drug exposure. The response comprises chromatin remodeling, activation of signaling cascades and markers implicated in cancer stemness with higher angiogenic potential and tumorigenicity. These changes are characterized by a common increase in CD271 expression concomitantly with loss of differentiation markers such as melan-A and tyrosinase, enhanced aldehyde dehydrogenase (ALDH) activity and upregulation of histone demethylases. Accordingly, IDTCs show a loss of H3K4me3, H3K27me3 and gain of H3K9me3 suggesting activation and repression of differential genes. Drug holidays at the IDTC state allow for reversion into parental cells re-sensitizing them to the drug they were primarily exposed to. However, upon continuous drug exposure IDTCs eventually transform into permanent and irreversible drug-resistant cells. Knockdown of CD271 or KDM5B decreases transition into the IDTC state substantially but does not prevent it. Targeting IDTCs would be crucial for sustainable disease management and prevention of acquired drug resistance.

    Topics: Animals; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Jumonji Domain-Containing Histone Demethylases; Melanoma; Mice; Nerve Tissue Proteins; Nuclear Proteins; Pyridones; Pyrimidinones; Receptors, Nerve Growth Factor; Repressor Proteins; Signal Transduction; Stress, Physiological

2015
MEK inhibitor-induced dusky erythema: characteristic drug hypersensitivity manifestation in 3 patients.
    JAMA dermatology, 2015, Volume: 151, Issue:1

    MEK inhibitors are being evaluated in clinical trials for treatment of different malignant neoplasms; trametinib dimethyl sulfoxide was approved by the US Food and Drug Administration for melanoma in 2013. We present 3 cases of patients receiving MEK inhibitors who developed an atypical eruption.. Three patients who were receiving different MEK inhibitors (selumetinib, cobimetinib, and trametinib) developed an eruption, all associated with unique duskiness. Drug hypersensitivity was confirmed by histopathologic testing in 2 of the 3 cases. The skin eruption responded well to corticosteroids and did not recur when treatment with the MEK inhibitor was restarted in 2 of the patients.. The typical skin reaction associated with MEK inhibitors is a papulopustular eruption. To our knowledge, the dusky erythema that occurred in the 3 patients described here has not previously been reported for this drug class.

    Topics: Adult; Azetidines; Benzimidazoles; Drug Eruptions; Erythema; Female; Glucocorticoids; Humans; Male; Melanoma; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

2015
Clinical and radiographic response with combined BRAF-targeted therapy in stage 4 ameloblastoma.
    Journal of the National Cancer Institute, 2015, Volume: 107, Issue:1

    Topics: Adult; Ameloblastoma; Antineoplastic Combined Chemotherapy Protocols; Black or African American; Compassionate Use Trials; Glutamic Acid; Humans; Imidazoles; Lung Neoplasms; Male; Mandibular Neoplasms; Molecular Targeted Therapy; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiography; Treatment Outcome; Valine

2015
Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer.
    Oncotarget, 2015, Jan-20, Volume: 6, Issue:2

    Attempts to directly block the mutant neuroblastoma rat sarcoma oncogene (NRAS) protein, a driving mutation in many cancer types, have been unsuccessful. Current treatments focus on inhibition of different components of NRAS' two main downstream cascades: PI3K/AKT/mTOR and MAPK. Here we test a novel dual therapy combination of metformin and trametinib on a panel of 16 NRAS mutant cell lines, including melanoma cells, melanoma cells with acquired trametinib resistance, lung cancer and neuroblastoma cells. We show that both of the main downstream cascades of NRAS can be blocked by this combination: metformin indirectly inhibits the PI3K/AKT/mTOR pathway and trametinib directly impedes the MAPK pathway. This dual therapy synergistically reduced cell viability in vitro and xenograft tumor growth in vivo. We conclude that metformin and trametinib combinations are effective in preclinical models and may be a possible option for treatment of NRAS mutant cancers.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; GTP Phosphohydrolases; Humans; Immunoblotting; MAP Kinase Signaling System; Membrane Proteins; Metformin; Mice, Nude; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; TOR Serine-Threonine Kinases; Tumor Burden; Xenograft Model Antitumor Assays

2015
The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2015, Apr-01, Volume: 21, Issue:7

    To assess the immunologic effects of dabrafenib and trametinib in vitro and to test whether trametinib potentiates or antagonizes the activity of immunomodulatory antibodies in vivo.. Immune effects of dabrafenib and trametinib were evaluated in human CD4(+) and CD8(+) T cells from healthy volunteers, a panel of human tumor cell lines, and in vivo using a CT26 mouse model.. Dabrafenib enhanced pERK expression levels and did not suppress human CD4(+) or CD8(+) T-cell function. Trametinib reduced pERK levels, and resulted in partial/transient inhibition of T-cell proliferation/expression of a cytokine and immunomodulatory gene subset, which is context dependent. Trametinib effects were partially offset by adding dabrafenib. Dabrafenib and trametinib in BRAF V600E/K, and trametinib in BRAF wild-type tumor cells induced apoptosis markers, upregulated HLA molecule expression, and downregulated certain immunosuppressive factors such as PD-L1, IL1, IL8, NT5E, and VEGFA. PD-L1 expression in tumor cells was upregulated after acquiring resistance to BRAF inhibition in vitro. Combinations of trametinib with immunomodulators targeting PD-1, PD-L1, or CTLA-4 in a CT26 model were more efficacious than any single agent. The combination of trametinib with anti-PD-1 increased tumor-infiltrating CD8(+) T cells in CT26 tumors. Concurrent or phased sequential treatment, defined as trametinib lead-in followed by trametinib plus anti-PD-1 antibody, demonstrated superior efficacy compared with anti-PD-1 antibody followed by anti-PD-1 plus trametinib.. These findings support the potential for synergy between targeted therapies dabrafenib and trametinib and immunomodulatory antibodies. Clinical exploration of such combination regimens is under way.

    Topics: Animals; Antineoplastic Agents; B7-H1 Antigen; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; CTLA-4 Antigen; Drug Synergism; Female; Humans; Imidazoles; Immunologic Factors; MAP Kinase Kinase Kinases; Mice; Mice, Inbred BALB C; Oximes; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2015
Hypoxia/HIF1α induces lapatinib resistance in ERBB2-positive breast cancer cells via regulation of DUSP2.
    Oncotarget, 2015, Feb-10, Volume: 6, Issue:4

    ERBB2/HER2 belongs to the EGFR-family of receptor tyrosine kinases and its overexpression can promote tumor progression. Breast cancer patients with ERBB2 amplifications are currently treated with lapatinib, a small-molecule kinase inhibitor that specifically blocks EGFR/ERBB2 signaling. Here, we show that hypoxia, via HIF-1, induces resistance to lapatinib-mediated effects in ERBB2-expressing mammary epithelial and ERBB2-positive breast cancer cells. Lapatinib-mediated growth inhibition and apoptosis in three-dimensional (3D) cultures are decreased under hypoxic conditions. Hypoxia can maintain activation of signaling pathways downstream from ERBB2 including AKT and ERK in the presence of lapatinib. HIF-1 is both required and sufficient to induce lapatinib resistance as overexpression of stable HIF-1 in ERBB2-expressing cells blocks lapatinib-mediated effects and maintains ERBB2-downstream signaling under normoxic conditions. Under hypoxia, activation of ERK signaling is required for lapatinib resistance as treatment with MEK inhibitor trametinib reverses hypoxia-mediated lapatinib resistance. HIF-1 can bypass the lapatinib-treated inhibition of the ERK pathway via inhibition of the dual-specificity phosphatase 2 (DUSP2). Indeed, overexpression of DUSP2 in ErbB2-positve breast cancer cells reverses hypoxia-mediated lapatinib resistance. Thus, our results provide rationale for therapeutic evaluation of the treatment of hypoxic ERBB2 expressing breast tumors with a combination of lapatinib and MEK inhibitors.

    Topics: Apoptosis; Breast Neoplasms; Cell Hypoxia; Cell Line; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Dual Specificity Phosphatase 2; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoblotting; Kaplan-Meier Estimate; Lapatinib; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Quinazolines; Receptor, ErbB-2; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction

2015
PD-L1 Expression and Tumor-Infiltrating Lymphocytes Define Different Subsets of MAPK Inhibitor-Treated Melanoma Patients.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2015, Jul-15, Volume: 21, Issue:14

    To evaluate the expression of tumor PD-L1 and changes in tumor-infiltrating lymphocyte (TIL) populations in patients with metastatic melanoma treated with targeted MAPK inhibitors.. Ninety-three tumors were analyzed from 40 patients treated with a BRAF inhibitor alone (BRAFi; n = 28) or combination of BRAF and MEK inhibitors (Combi; n = 12). Tumors were excised before treatment (PRE), early during treatment (EDT), and at progression (PROG). Immunohistochemical staining was performed for CD4, CD8, CD68, FOXP3, LAG3, PD-1, and PD-L1 and correlated with clinical outcome.. Patients' tumors that were PD-L1 positive at baseline showed a significant decrease in PD-L1 expression at PROG (P = 0.028), whereas patients' tumors that were PD-L1 negative at baseline showed a significant increase in PD-L1 expression at PROG (P = 0.008) irrespective of treatment with BRAFi or Combi. Overall PD-L1 expression highly correlated with TIL immune markers. BRAFi-treated patients showed significant increases in CD4(+), CD8(+), and PD-1(+) lymphocytes from PRE to EDT (P = 0.001, P = 0.001, P = 0.017, respectively), and Combi-treated patients showed similar increases in CD4(+) and CD8(+) lymphocytes from PRE to EDT (P = 0.017, P = 0.021).. The addition of MEKi to BRAFi did not result in significant reduction in immune infiltration in EDT biopsies. This provides support for conducting trials that combine MAPKi with immune checkpoint inhibitors in the hope of improving complete and durable response rates. PD-L1 expression at PROG on MAPK inhibitors varied according to baseline expression suggesting that combining MAPKi with immunotherapies concurrently may be more effective in patients with PD-L1 expression and TILs in baseline melanoma samples.

    Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; B7-H1 Antigen; Female; Humans; Imidazoles; Immunohistochemistry; Indoles; Kaplan-Meier Estimate; Lymphocytes, Tumor-Infiltrating; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Oximes; Proportional Hazards Models; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib; Young Adult

2015
Antitumour efficacy of the selumetinib and trametinib MEK inhibitors in a combined human airway-tumour-stroma lung cancer model.
    Journal of biotechnology, 2015, Jul-10, Volume: 205

    With more than 1 million deaths worldwide every year, lung cancer remains an area of unmet need. Accessible human in vitro 3D tissue models are required to improve preclinical predictivity. OncoCilAir™ is a new in vitro model of Non Small Cell Lung Cancer which combines a reconstituted human airway epithelium, human lung fibroblasts and lung adenocarcinoma cell lines. Remarkably, we found that in this 3D microenvironment tumour cells expand by forming nodules, mimicking a human lung cancer feature. OncoCilAir™ mutated for KRAS and expressing the green fluorescent protein were used to test the antitumour potential of the investigational MEK inhibitors selumetinib and trametinib. As primary endpoint, changes in tumour size were assessed by fluorescence measurements. Tumours showed a reduced growth in response to the MEK inhibitors, but halting the selumetinib dosing resulted in tumour relapse. Importantly, toxicity study on the normal part of the cultures revealed that the airway epithelium integrity was also affected by anticancer drug treatments. These results highlight the possibility to assess simultaneously drug efficacy, drug side-effect and tumour recurrence within a single culture model. OncoCilAir™ heralds a new generation of integrated in vitro tumour models that should be valuable tools for drug development, while reducing animal testing.

    Topics: Benzimidazoles; Cell Proliferation; Cells, Cultured; Drug Screening Assays, Antitumor; Epithelial Cells; Fibroblasts; Humans; Lung; Lung Neoplasms; Models, Biological; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Tumor Microenvironment

2015
Successful (neo)adjuvant BRAF-targeted therapy in a patient with locally advanced BRAF V600E mutant melanoma.
    Melanoma research, 2015, Volume: 25, Issue:2

    The treatment of locally advanced metastasized melanoma is challenging because there is no level 1 evidence to guide clinical decision-making. Moreover, the treatment options available fail to improve overall survival and are associated with considerable morbidity. Here, we show that systemic treatment with BRAF inhibitor vemurafenib substituted by dual BRAF/MEK inhibition (dabrafenib and trametinib) before surgery can offer the potential to cure the initially difficult or inoperable melanoma. A 62-year-old woman was diagnosed with an AJCC stage IIIB melanoma harboring the BRAF V600E mutation after a complete initial evaluation. Clinically, the patient presented a large primary lesion that was surrounded by ∼25 secondary epidermotropic lesions both satellite and 'in transit' with a diameter between 1 and 6 mm. Following multidisciplinary consultation, the patient was started on 960 mg twice-daily vemurafenib, which was stopped and resumed at 720 mg twice daily, and finally substituted with the combination dabrafenib and trametinib to reduce the persistent side effects. Successive clinical examinations had shown a progressive reduction in the thickness of the melanoma lesions. After about 5 months of therapy, surgery was performed and the histopathological analysis showed an almost complete regression of tumor cells. The treatment with dabrafenib/trametinib was continued only 3 months after surgery and stopped at the patient's request. The patient currently remains in complete remission at 8 months after surgery. The case presented here supports the use of neoadjuvant treatment with BRAF inhibitors in advanced 'in transit' melanoma.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Drug Substitution; Female; Genetic Predisposition to Disease; Humans; Imidazoles; Indoles; Melanoma; Middle Aged; Molecular Targeted Therapy; Mutation; Neoadjuvant Therapy; Oximes; Phenotype; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Time Factors; Treatment Outcome; Vemurafenib

2015
Trametinib, a novel MEK kinase inhibitor, suppresses lipopolysaccharide-induced tumor necrosis factor (TNF)-α production and endotoxin shock.
    Biochemical and biophysical research communications, 2015, Mar-13, Volume: 458, Issue:3

    Lipopolysaccharide (LPS), one of the most prominent pathogen-associated molecular patterns (PAMPs), activates macrophages, causing release of toxic cytokines (i.e. tumor necrosis factor (TNF)-α) that may provoke inflammation and endotoxin shock. Here, we tested the potential role of trametinib, a novel and highly potent MAPK/ERK kinase (MEK) inhibitor, against LPS-induced TNF-α response in monocytes, and analyzed the underlying mechanisms. We showed that trametinib, at nM concentrations, dramatically inhibited LPS-induced TNF-α mRNA expression and protein secretion in transformed (RAW 264.7 cells) and primary murine macrophages. In ex-vivo cultured human peripheral blood mononuclear cells (PBMCs), this MEK inhibitor similarly suppressed TNF-α production by LPS. For the mechanism study, we found that trametinib blocked LPS-induced MEK-ERK activation in above monocytes, which accounted for the defective TNF-α response. Macrophages or PBMCs treated with a traditional MEK inhibitor PD98059 or infected with MEK1/2-shRNA lentivirus exhibited a similar defect as trametinib, and nullified the activity of trametinib. On the other hand, introducing a constitutively-active (CA) ERK1 restored TNF-α production by LPS in the presence of trametinib. In vivo, mice administrated with trametinib produced low levels of TNF-α after LPS stimulation, and these mice were protected from LPS-induced endotoxin shock. Together, these results show that trametinib inhibits LPS-induced TNF-α expression and endotoxin shock probably through blocking MEK-ERK signaling.

    Topics: Adult; Animals; Cell Line; Cells, Cultured; Humans; Leukocytes, Mononuclear; Lipopolysaccharides; Macrophages; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Shock, Septic; Tumor Necrosis Factor-alpha; Young Adult

2015
Removing a hair of doubt about BRAF targeting.
    Blood, 2015, Feb-19, Volume: 125, Issue:8

    In this issue of Blood, Pettirossi et al, including Drs Tiacci and Falini, who led the effort in 2011 defining the BRAF-V600E driving mutation in hairy cell leukemia (HCL),provide extensive laboratory studies showing that inhibitors of BRAF-V600E and/or mitogen-activated protein kinase kinase (MEK) reach their targets and cause HCL cell death

    Topics: Antineoplastic Agents; Humans; Imidazoles; Indoles; Leukemia, Hairy Cell; Oximes; Pyridones; Pyrimidinones; Sulfonamides; Transcriptome; Vemurafenib

2015
Trametinib with or without vemurafenib in BRAF mutated non-small cell lung cancer.
    PloS one, 2015, Volume: 10, Issue:2

    V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) mutated lung cancer is relatively aggressive and is resistant to currently available therapies. In a recent phase II study for patients with BRAF-V600E non-small cell lung cancer (NSCLC), BRAF V600E inhibitor demonstrated evidence of activity, but 30% of this selected group progressed while on treatment, suggesting a need for developing alternative strategies. We tested two different options to enhance the efficacy of vemurafenib (BRAF V600E inhibitor) in BRAF mutated NSCLC. The first option was the addition of erlotinib to vemurafenib to see whether the combination provided synergy. The second was to induce MEK inhibition (downstream of RAF) with trametinib (MEK inhibitor). We found that the combination of vemurafenib and erlotinib was not synergistic to the inhibition of p-ERK signaling in BRAF-V600E cells. Vemurafenib caused significant apoptosis, G1 arrest and upregulation of BIM in BRAF-V600 cells. Trametinib was effective as a single agent in BRAF mutated cells, either V600E or non-V600E. Finally, the combination of vemurafenib and trametinib caused a small but significant increase in apoptosis as well as a significant upregulation of BIM when compared to either single agent. Thus, hinting at the possibility of utilizing a combinational approach for the management of this group of patients. Importantly, trametinib alone caused upregulation of p-AKT in BRAF non-V600 mutated cells, while this effect was nullified with the combination. This finding suggests that, the combination of a MEK inhibitor with a BRAF inhibitor will be more efficacious in the clinical setting for patients with BRAF mutated NSCLC.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Erlotinib Hydrochloride; G1 Phase; Humans; Indoles; Lung Neoplasms; MAP Kinase Signaling System; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Quinazolines; Sulfonamides; Up-Regulation; Vemurafenib

2015
Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma.
    Science translational medicine, 2015, Mar-18, Volume: 7, Issue:279

    Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAF(V600E)-driven melanoma, SM1, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors, and improved in vivo cytotoxicity. Single-agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.

    Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; CTLA-4 Antigen; Humans; Imidazoles; Immunotherapy; Major Histocompatibility Complex; MAP Kinase Kinase Kinases; Melanoma; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oximes; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2015
Clinical observation of panniculitis in two patients with BRAF-mutated metastatic melanoma treated with a combination of a BRAF inhibitor and a MEK inhibitor.
    European journal of dermatology : EJD, 2015, Volume: 25, Issue:2

    Treatment with selective BRAF or MEK inhibitors is frequently associated with cutaneous toxicities, including squamous cell carcinoma (SCC), papillomas and rash. These cutaneous adverse effects are typically observed at a lower incidence during combined BRAF and MEK inhibitor therapy.. Two male patients with stage IV metastatic BRAF-mutated melanoma were treated with a combination of a selective BRAF inhibitor and a selective MEK inhibitor (dabrafenib and trametinib, or encorafenib (LGX818) and binimetinib (MEK162)) within two different clinical trials. Ten and 150 days after treatment start respectively, the patients developed painful nodules on the legs. In addition, one patient developed symmetrical articulation pain and intermittent fever episodes.. Based on the clinical and histological presentation, erythema nodosum-like panniculitis was diagnosed in both cases. No other aetiology could be found. After receiving topical or oral steroid treatment and anti-inflammatory analgesics, the painful nodular lesions disappeared several weeks later. In one case, a rebound of the painful nodules was observed when the combination treatment (dabrafenib and trametinib) was resumed after a 1-week unscheduled treatment interruption.. Panniculitis has previously been described in association with BRAF inhibitor treatment, but not MEK inhibitor treatment. Combination treatment is usually associated with a lower incidence of cutaneous adverse events (AEs), as compared to monotherapy. Panniculitis was observed in two patients during combined BRAF and MEK inhibitor treatment. These cases illustrate the need for further research in a larger patient population to identify a possible link between combined BRAF and MEK inhibitor treatment and the incidence of panniculitis.

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Humans; Imidazoles; Male; Melanoma; Mitogen-Activated Protein Kinases; Oximes; Panniculitis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides

2015
Discussion.
    Journal of the American College of Surgeons, 2015, Volume: 220, Issue:4

    Topics: Female; Humans; Imidazoles; Male; Melanoma; Mitogen-Activated Protein Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2015
Vemurafenib/dabrafenib and trametinib.
    British journal of clinical pharmacology, 2015, Volume: 80, Issue:4

    Topics: Antineoplastic Agents; Drug Therapy, Combination; Humans; Imidazoles; Indoles; MAP Kinase Signaling System; Melanoma; Oximes; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2015
Antitumor activity of the MEK inhibitor trametinib on intestinal polyp formation in Apc(Δ716) mice involves stromal COX-2.
    Cancer science, 2015, Volume: 106, Issue:6

    Extracellular signal-regulated kinase is an MAPK that is most closely associated with cell proliferation, and the MEK/ERK signaling pathway is implicated in various human cancers. Although epidermal growth factor receptor, KRAS, and BRAF are considered major targets for colon cancer treatment, the precise roles of the MEK/ERK pathway, one of their major downstream effectors, during colon cancer development remain to be determined. Using Apc(Δ716) mice, a mouse model of familial adenomatous polyposis and early-stage sporadic colon cancer formation, we show that MEK/ERK signaling is activated not only in adenoma epithelial cells, but also in tumor stromal cells including fibroblasts and vascular endothelial cells. Eight-week treatment of Apc(Δ716) mice with trametinib, a small-molecule MEK inhibitor, significantly reduced the number of polyps in the large size class, accompanied by reduced angiogenesis and tumor cell proliferation. Trametinib treatment reduced the COX-2 level in Apc(Δ716) tumors in vivo and in primary culture of intestinal fibroblasts in vitro. Antibody array analysis revealed that trametinib and the COX-2 inhibitor rofecoxib both reduced the level of CCL2, a chemokine known to be essential for the growth of Apc mutant polyps, in intestinal fibroblasts in vitro. Consistently, trametinib treatment reduced the Ccl2 mRNA level in Apc(Δ716) tumors in vivo. These results suggest that MEK/ERK signaling plays key roles in intestinal adenoma formation in Apc(Δ716) mice, at least in part, through COX-2 induction in tumor stromal cells.

    Topics: Animals; Antineoplastic Agents; Chemokine CCL2; Cyclooxygenase 2; Disease Models, Animal; Female; Genes, APC; Intestinal Polyps; Male; Mice; Mitogen-Activated Protein Kinase Kinases; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2015
Response of head and neck squamous cell carcinoma cells carrying PIK3CA mutations to selected targeted therapies.
    JAMA otolaryngology-- head & neck surgery, 2015, Volume: 141, Issue:6

    The PIK3CA mutation is one of the most common mutations in head and neck squamous cell carcinoma (HNSCC). Through this research we attempt to elicit the role of oncogene dependence and effects of targeted therapy on this PIK3CA mutation.. (1) To determine the role of oncogene dependence on PIK3CA-one of the more common and targetable oncogenes in HNSCC, and (2) to evaluate the consequence of this oncogene on the effectiveness of newly developed targeted therapies.. This was a cell culture-based, in vitro study performed at an academic research laboratory assessing the viability of PIK3CA-mutated head and neck cell lines when treated with targeted therapy.. PIK3CA-mutated head and neck cell lines were treated with 17-AAG, GDC-0941, trametinib, and BEZ-235.. Assessment of cell viability of HNSCC cell lines characterized for PIK3CA mutations or SCC25 cells engineered to express the PIK3CA hotspot mutations E545K or H1047R.. Surprisingly, in engineered cell lines, the hotspot E545K and H1047R mutations conferred increased, rather than reduced, IC50 assay measurements when treated with the respective HSP90, PI3K, and MEK inhibitors, 17-AAG, GDC-0941, and trametinib, compared with the SCC25 control cell lines. When treated with BEZ-235, H1047R-expressing cell lines showed increased sensitivity to inhibition compared with control, whereas those expressing E545K showed slightly increased sensitivity of unclear significance.. (1) The PIK3CA mutations within our engineered cell model did not lead to enhanced oncogene-dependent cell death when treated with direct inhibition of the PI3K enzyme yet did show increased sensitivity compared with control with dual PI3K/mTOR inhibition. (2) Oncogene addiction to PIK3CA hotspot mutations, if it occurs, is likely to evolve in vivo in the context of additional molecular changes that remain to be identified. Additional study is required to develop new model systems and approaches to determine the role of targeted therapy in the treatment of PI3K-overactive HNSCC tumors.

    Topics: Benzoquinones; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Class I Phosphatidylinositol 3-Kinases; Head and Neck Neoplasms; Humans; Imidazoles; Indazoles; Inhibitory Concentration 50; Lactams, Macrocyclic; Molecular Targeted Therapy; Mutation; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Pyridones; Pyrimidinones; Quinolines; Squamous Cell Carcinoma of Head and Neck; Sulfonamides; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

2015
MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis.
    Genes, chromosomes & cancer, 2015, Volume: 54, Issue:6

    Langerhans cell histiocytosis (LCH) is now understood to be a neoplastic disease in which over 50% of cases have somatic activating mutations of BRAF. However, the extracellular signal-related (ERK) pathway is activated in all cases including those with wild type BRAF alleles. Here, we applied a targeted massively parallel sequencing panel to 30 LCH samples to test for the presence of additional genetic alterations that might cause ERK pathway activation. In 20 BRAF wild type samples, we found 3 somatic mutations in MAP2K1 (MEK1) including C121S and C121S/G128D in the kinase domain, and 56_61QKQKVG>R, an in-frame deletion in the N-terminal regulatory domain. All three variant proteins constitutively phosphorylated ERK in in vitro kinase assays. The C121S/G128D and 56_61QKQKVG>R variants were resistant to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib in vitro. Within the entire sample set, we found 3 specimens with mutations in MAP3K1 (MEKK1), including two truncation mutants, T779fs and T1481fs; T1481fs encoded an unstable and nonfunctional protein when expressed in vitro. T779fs was present in a specimen carrying BRAF V600E. The third variant was a single nucleotide substitution, E1286V, which was fully functional and is likely a germline polymorphism. These results indicate that LCH cells can harbor additional genetic alterations in the RAS-RAF-MEK pathway which, in the case of MAP2K1, may be responsible for ERK activation in a wild type BRAF setting. The resistance of some of these variants to trametinib may also have clinical implications for the combined use of RAF and MEK inhibitors in LCH.

    Topics: Antineoplastic Agents; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase Kinase 1; Mutation; Phosphorylation; Pyridones; Pyrimidinones; Signal Transduction

2015
Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter.
    Oncotarget, 2015, Jun-20, Volume: 6, Issue:17

    Overexpression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is one of the main reasons of multidrug resistance (MDR) in cancer cells. Trametinib, a novel specific small-molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, is currently used for the treatment of melanoma in clinic. In this study, we investigated the effect of trametinib on MDR mediated by ABC transporters. Trametinib significantly potentiated the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in cancer cells overexpressed ABCB1, but not ABCC1 and ABCG2. Furthermore, trametinib did not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, trametinib potently blocked the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. Importantly, trametinib remarkably enhanced the effect of vincristine against the xenografts of ABCB1-overexpressing cancer cells in nude mice. The predicted binding mode showed the hydrophobic interactions of trametinib within the large drug binding cavity of ABCB1. Consequently, our findings may have important implications for use of trametinib in combination therapy for cancer treatment.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Breast Neoplasms; Cell Cycle Checkpoints; Cell Line, Tumor; Cisplatin; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Docking Simulation; Moths; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Pyridones; Pyrimidinones; Rhodamine 123; Vincristine; Xenograft Model Antitumor Assays

2015
Epithelial to mesenchymal transition is associated with rapamycin resistance.
    Oncotarget, 2015, Aug-14, Volume: 6, Issue:23

    Rapamycin analogues have antitumor efficacy in several tumor types, however few patients demonstrate tumor regression. Thus, there is a pressing need for markers of intrinsic response/resistance and rational combination therapies. We hypothesized that epithelial-to-mesenchymal transition (EMT) confers rapamycin resistance. We found that the epithelial marker E-cadherin protein is higher in rapamycin sensitive (RS) cells and mesenchymal breast cancer cell lines selected by transcriptional EMT signatures are less sensitive to rapamycin. MCF7 cells, transfected with constitutively active mutant Snail, had increased rapamycin resistance (RR) compared to cells transfected with wild-type Snail. Conversely, we transfected two RR mesenchymal cell lines-ACHN and MDA-MB-231-with miR-200b/c or ZEB1 siRNA to promote mesenchymal-to-epithelial transition. This induced E-cadherin expression in both cell lines, and ACHN demonstrated a significant increase in RS. Treatment of ACHN and MDA-MB-231 with trametinib modulated EMT in ACHN cells in vitro. Treatment of MDA-MB-231 and ACHN xenografts with trametinib in combination with rapamycin resulted in significant growth inhibition in both but without an apparent effect on EMT. Future studies are needed to determine whether EMT status is predictive of sensitivity to rapalogs and to determine whether combination therapy with EMT modulating agents can enhance antitumor effects of PI3K/mTOR inhibitors.

    Topics: Animals; Antigens, CD; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cadherins; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Extracellular Signal-Regulated MAP Kinases; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Homeodomain Proteins; Humans; MCF-7 Cells; Mice, Nude; MicroRNAs; Mitogen-Activated Protein Kinase Kinases; Mutation; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; RNA Interference; Sirolimus; Snail Family Transcription Factors; Time Factors; TOR Serine-Threonine Kinases; Transcription Factors; Transfection; Tumor Burden; Xenograft Model Antitumor Assays; Zinc Finger E-box-Binding Homeobox 1

2015
Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma.
    Cancer research, 2015, Jul-01, Volume: 75, Issue:13

    Uveal melanoma patients with metastatic disease usually die within one year, emphasizing an urgent need to develop new treatment strategies for this cancer. MEK inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in metastatic uveal melanoma patients. In this study, we screened for growth factors that elicited resistance in newly characterized metastatic uveal melanoma cell lines to clinical-grade MEK inhibitors, trametinib and selumetinib. We show that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1 and sustained HGF-mediated activation of AKT. Individually targeting ERBB3 and cMET, the receptors for NRG1 and HGF, respectively, overcome resistance to trametinib provided by these growth factors and by conditioned medium from fibroblasts that produce NRG1 and HGF. Inhibition of AKT also effectively reverses the protective effect of NRG1 and HGF in trametinib-treated cells. Uveal melanoma xenografts growing in the liver in vivo and a subset of liver metastases of uveal melanoma patients express activated forms of ERBB2 (the coreceptor for ERBB3) and cMET. Together, these results provide preclinical evidence for the use of MEK inhibitors in combination with clinical-grade anti-ERBB3 or anti-cMET monoclonal antibodies in metastatic uveal melanoma.

    Topics: Animals; Benzimidazoles; Cell Line, Tumor; Drug Resistance, Neoplasm; Hepatocyte Growth Factor; Humans; MAP Kinase Kinase Kinases; Melanoma; Mice; Neuregulin-1; Proto-Oncogene Proteins c-met; Pyridones; Pyrimidinones; Receptor, ErbB-3; Tumor Cells, Cultured; Uveal Neoplasms; Xenograft Model Antitumor Assays

2015
Severe gastrointestinal toxicity with administration of trametinib in combination with dabrafenib and ipilimumab.
    Pigment cell & melanoma research, 2015, Volume: 28, Issue:5

    Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colitis; Colon; Female; Humans; Imidazoles; Immunotherapy; Ipilimumab; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

2015
Selective Targeting of CTNBB1-, KRAS- or MYC-Driven Cell Growth by Combinations of Existing Drugs.
    PloS one, 2015, Volume: 10, Issue:5

    The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. Preferably, drug combinations are synergistic rather than additive, and, ideally, drug combinations work synergistically only in cancer cells and not in non-malignant cells. We have developed a workflow to identify such targeted synergies, and applied this approach to selectively inhibit the proliferation of cell lines with mutations in genes that are difficult to modulate with small molecules. The approach is based on curve shift analysis, which we demonstrate is a more robust method of determining synergy than combination matrix screening with Bliss-scoring. We show that the MEK inhibitor trametinib is more synergistic in combination with the BRAF inhibitor dabrafenib than with vemurafenib, another BRAF inhibitor. In addition, we show that the combination of MEK and BRAF inhibitors is synergistic in BRAF-mutant melanoma cells, and additive or antagonistic in, respectively, BRAF-wild type melanoma cells and non-malignant fibroblasts. This combination exemplifies that synergistic action of drugs can depend on cancer genotype. Next, we used curve shift analysis to identify new drug combinations that specifically inhibit cancer cell proliferation driven by difficult-to-drug cancer genes. Combination studies were performed with compounds that as single agents showed preference for inhibition of cancer cells with mutations in either the CTNNB1 gene (coding for β-catenin), KRAS, or cancer cells expressing increased copy numbers of MYC. We demonstrate that the Wnt-pathway inhibitor ICG-001 and trametinib acted synergistically in Wnt-pathway-mutant cell lines. The ERBB2 inhibitor TAK-165 was synergistic with trametinib in KRAS-mutant cell lines. The EGFR/ERBB2 inhibitor neratinib acted synergistically with the spindle poison docetaxel and with the Aurora kinase inhibitor GSK-1070916 in cell lines with MYC amplification. Our approach can therefore efficiently discover novel drug combinations that selectively target cancer genes.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Aza Compounds; Benzimidazoles; beta Catenin; Cell Line, Tumor; Cell Proliferation; Humans; Imidazoles; Indazoles; Indoles; Melanoma; Molecular Targeted Therapy; Mutation; Oxazoles; Oximes; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Quinolines; Sulfonamides; Triazoles; Vemurafenib

2015
Clinical activity of the MEK inhibitor trametinib in metastatic melanoma containing BRAF kinase fusion.
    Pigment cell & melanoma research, 2015, Volume: 28, Issue:5

    Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Brain Neoplasms; Carrier Proteins; Disease Progression; DNA Mutational Analysis; Female; Humans; Intracellular Signaling Peptides and Proteins; Magnetic Resonance Imaging; Male; MAP Kinase Kinase Kinases; Melanoma; Membrane Proteins; Middle Aged; Neoplasm Metastasis; Oncogene Proteins, Fusion; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2015
EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition.
    International journal of oncology, 2015, Volume: 47, Issue:2

    Since the prognosis of unresectable advanced gastric cancer remains poor, novel therapeutic strategies are needed. Somatic MEK1 gene mutations have been reported as oncogenic activating mutations in gastric cancer, and MEK inhibitors can be effective against such gastric cancers. In the present study, however, activated EGFR and HER2 signals after treatment with a MEK inhibitor (trametinib) were found in a MEK1-mutated gastric cancer cell line (OCUM-1 cell line) using a phospho-receptor tyrosine kinase array. The phosphorylation of EGFR and HER2 reactivated ERK1/2, which had been inhibited by trametinib, and EGF stimulation led to resistance to trametinib in this cell line. Lapatinib, an EGFR and an HER2 inhibitor, reversed the activation of ERK1/2 by inhibiting the phosphorylation of EGFR and HER2 and cancelled the resistance. The combination of trametinib and lapatinib synergistically inhibited the cell growth of the OCUM-1 cell line and strongly induced apoptosis by inhibiting the activated EGFR and HER2 signals. These results suggest that the EGFR and HER2 signals play a salvage role and are related to resistance to MEK inhibitors in MEK1‑mutated gastric cancer. Moreover, combination therapy with trametinib and lapatinib can exhibit a synergistic effect and may contribute to overcoming the resistance to MEK inhibitors.

    Topics: Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Humans; Lapatinib; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mutation; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Quinazolines; Receptor, ErbB-2; Stomach Neoplasms

2015
The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity.
    Cell, 2015, Jul-02, Volume: 162, Issue:1

    Identifying the molecular mechanisms that underlie aging and their pharmacological manipulation are key aims for improving lifelong human health. Here, we identify a critical role for Ras-Erk-ETS signaling in aging in Drosophila. We show that inhibition of Ras is sufficient for lifespan extension downstream of reduced insulin/IGF-1 (IIS) signaling. Moreover, direct reduction of Ras or Erk activity leads to increased lifespan. We identify the E-twenty six (ETS) transcriptional repressor, Anterior open (Aop), as central to lifespan extension caused by reduced IIS or Ras attenuation. Importantly, we demonstrate that adult-onset administration of the drug trametinib, a highly specific inhibitor of Ras-Erk-ETS signaling, can extend lifespan. This discovery of the Ras-Erk-ETS pathway as a pharmacological target for animal aging, together with the high degree of evolutionary conservation of the pathway, suggests that inhibition of Ras-Erk-ETS signaling may provide an effective target for anti-aging interventions in mammals.

    Topics: Aging; Animals; Drosophila melanogaster; Drosophila Proteins; Eye Proteins; Insulin Receptor Substrate Proteins; Longevity; MAP Kinase Signaling System; Models, Animal; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Repressor Proteins

2015
Correction: Selective Targeting of CTNNB1-, KRAS- or MYC-Driven Cell Growth by Combinations of Existing Drugs.
    PloS one, 2015, Volume: 10, Issue:6

    Topics: beta Catenin; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Imidazoles; Indoles; Mutation; Oximes; Proto-Oncogene Proteins c-myb; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2015
Trametinib radiosensitises RAS- and BRAF-mutated melanoma by perturbing cell cycle and inducing senescence.
    Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2015, Volume: 117, Issue:2

    Radiotherapy (RT) is used frequently in patients with melanoma, but results are suboptimal because the disease is often radioresistant. This may be due to constitutive activation of MAPK pathway signalling through mutations involving RAS/RAF. Thus, we studied whether trametinib, a potent and selective allosteric inhibitor of MEK1/2 could improve the efficacy of RT.. Clonogenic survival assays were performed in human BRAF-mutant (A375), NRAS-mutant (D04, WM1631), KRAS-mutant (WM1791c) and wild-type (PMWK) melanoma cell lines. The effects of trametinib with and without radiation on protein levels of MEK effectors were measured by immunoblot analyses. Cell cycle effects, DNA damage repair, mitotic catastrophe and senescence were measured using flow cytometry, γH2Ax staining, nuclear fragmentation and β-galactosidase staining, respectively. Additionally, athymic mice with D04 flank tumours were treated with fractionated RT after gavage with trametinib and monitored for tumour growth.. All cell lines, except PMWK, exhibited enhanced cytotoxicity when RT was combined with trametinib compared to either agent alone. Sensitiser enhancement ratios were 1.70, 1.32, 1.10, and 1.70 for A375, D04, WM1361 and WM1791c, respectively. Trametinib efficiently blocked RT-induced phosphorylation of ERK at nanomolar concentrations. Increased radiosensitivity correlated with prolonged G1 arrest and reduction in the radioresistant S phase up to 48 h following RT. A larger population of senescence-activated β-galactosidase-positive cells was seen in the trametinib pretreated group, and this correlated with activation of two of the major mediators of induced senescence, p53 and pRb. Mice receiving the combination treatment (trametinib 1mg/kg and RT over 3 days) showed a reduced mean tumour volume compared with mice receiving trametinib alone (p=0.016), or RT alone (p=0.047). No overt signs of drug toxicity were observed.. Trametinib radiosensitised RAS-/RAF-mutated melanoma cells by inducing prolonged G1 arrest and premature senescence. In this pre-clinical study we demonstrate that combining trametinib and RT is well tolerated, and reduces tumour growth in vivo.

    Topics: Aging; Animals; Cell Cycle; Female; MAP Kinase Signaling System; Melanoma, Experimental; Mice; Mice, Nude; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Radiation-Sensitizing Agents; ras Proteins

2015
Trametinib-induced Left Ventricular Dysfunction in a Child With Relapsed Neuroblastoma.
    Journal of pediatric hematology/oncology, 2015, Volume: 37, Issue:6

    The MEK inhibitor trametinib is globally approved for metastatic melanoma harboring BRAF mutations. There are no reports thus far on its use in children. Exome sequencing on a relapsed tumor sample from an 11-year-old male with progressive, multiply relapsed stage 4 neuroblastoma revealed NRASQ61K mutation. After demonstration of normal cardiac function, he was started on oral trametinib. On day 13 of treatment, echocardiogram showed moderate left ventricular dysfunction. Trametinib was discontinued on day 15 and oral lisinopril was started. Left ventricular function recovered to baseline 37 days after discontinuing trametinib. However, neuroblastoma showed further progression.

    Topics: Child; GTP Phosphohydrolases; Humans; Male; Membrane Proteins; Mutation; Neoplasm Recurrence, Local; Neuroblastoma; Prognosis; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Ventricular Dysfunction, Left

2015
Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma.
    JAMA dermatology, 2015, Volume: 151, Issue:10

    The cutaneous adverse effects of the BRAF inhibitors vemurafenib and dabrafenib mesylate in the treatment of metastatic melanoma have been well reported. The addition of a MEK inhibitor to a BRAF inhibitor improves the blockade of the mitogen-activated protein kinase pathway. The combination of dabrafenib with the MEK inhibitor trametinib dimethyl sulfoxide (CombiDT therapy) increases response rate and survival compared with a BRAF inhibitor alone. Clinical trials have suggested that CombiDT therapy induces fewer cutaneous toxic effects than a single-agent BRAF inhibitor. To our knowledge, a direct comparison has not been performed before.. To compare the cutaneous toxic effects of BRAF inhibitor monotherapy and CombiDT therapy in a large cohort of patients.. We performed a retrospective cohort study from September 1, 2009, through November 30, 2013. The study population included 185 Australian patients with unresectable stages IIIC and IV melanoma referred from Crown Princess Mary Cancer Care Centre who underwent review at the Department of Dermatology, Westmead Hospital. Of these, 119 patients received dabrafenib; 36, vemurafenib; and 30, CombiDT therapy. Data analysis were performed in December 2013.. Multiple cutaneous adverse effects between BRAF inhibitor monotherapy and CombiDT therapy were identified and compared in a cohort of patients who underwent the same dermatologic assessment.. The most common cutaneous adverse effects seen in patients receiving the single-agent BRAF inhibitor dabrafenib or vemurafenib included Grover disease (51 patients [42.9%] and 14 [38.9%], respectively [P = .67]), plantar hyperkeratosis (47 [39.5%] and 14 [38.9%], respectively [P = .95]), verrucal keratosis (79 [66.4%] and 26 [72.2%], respectively [P = .51]), and cutaneous squamous cell carcinoma (31 [26.1%] and 13 [36.1%], respectively [P = .54]). Photosensitivity was more common with vemurafenib (14 patients [38.9%]) compared with dabrafenib (1 [0.8%]; P < .001). Compared with dabrafenib, CombiDT therapy showed a higher frequency of folliculitis (12 patients [40.0%] vs. 8 [6.7%]; P < .001) and a significant decrease of cutaneous squamous cell carcinoma (0 vs. 31 [26.1%]; P < .001), verrucal keratosis (0 vs. 79 [66.4%]; P < .001), and Grover disease (0 vs. 51 [42.9%]; P < .001).. This study confirms that the prevalence of cutaneous toxic effects differs among vemurafenib, dabrafenib, and CombiDT therapies. Cutaneous squamous cell carcinoma is the most concerning cutaneous toxic effect related to BRAF inhibitor monotherapy that did not appear with CombiDT therapy. Although CombiDT therapy has an improved profile of cutaneous toxic effects, continuous dermatologic assessments should be provided for all patients when receiving these treatments.

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Oximes; Prevalence; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Diseases; Skin Neoplasms; Sulfonamides; Vemurafenib

2015
Combination of antibodies directed against different ErbB3 surface epitopes prevents the establishment of resistance to BRAF/MEK inhibitors in melanoma.
    Oncotarget, 2015, Sep-22, Volume: 6, Issue:28

    Patients with metastatic melanoma bearing V600 mutations in BRAF oncogene clinically benefit from the treatment with BRAF inhibitors alone or in combination with MEK inhibitors. However, a limitation to such treatment is the occurrence of resistance. Tackling the adaptive changes helping cells survive from drug treatment may offer new therapeutic opportunities. Very recently the ErbB3 receptor has been shown to act as a central node promoting survival of BRAF mutated melanoma. In this paper we first demonstrate that ErbB3/AKT hyperphosphorylation occurs in BRAF mutated melanoma cell lines following exposure to BRAF and/or MEK inhibitors. This strongly correlates with increased transcriptional activation of its ligand neuregulin. Anti-ErbB3 antibodies impair the establishment of de novo cell resistance to BRAF inhibition in vitro. In order to more potently ablate ErbB3 activity we used a combination of two anti-ErbB3 antibodies directed against distinct epitopes of its extracellular domain. These two antibodies in combo with BRAF/MEK inhibitors potently inhibit in vitro cell growth and tumor regrowth after drug withdrawal in an in vivo xenograft model. Importantly, residual tumor masses from mice treated by the antibodies and BRAF/ERK inhibitors combo are characterized almost exclusively by large necrotic areas with limited residual areas of tumor growth. Taken together, our findings support the concept that triple therapy directed against BRAF/MEK/ErbB3 may be able to provide durable control of BRAF mutated metastatic melanoma.

    Topics: Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Epitopes; Humans; Indoles; MAP Kinase Kinase 1; Melanoma; Mice; Mutation; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Receptor, ErbB-3; Sulfonamides; Vemurafenib; Xenograft Model Antitumor Assays

2015
Clinicopathologic features associated with efficacy and long-term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors.
    Cancer, 2015, Nov-01, Volume: 121, Issue:21

    The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown.. For 142 consecutive immunotherapy- and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n = 111) or a combination of dabrafenib and trametinib (n = 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival.. The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31; P < .001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients.. Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Drug Therapy, Combination; Female; Follow-Up Studies; Genotype; Humans; Imidazoles; Indoles; L-Lactate Dehydrogenase; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sex Factors; Skin Neoplasms; Sulfonamides; Survival Rate; Treatment Outcome; Vemurafenib; Young Adult

2015
Repurposing of anticancer drugs: in vitro and in vivo activities against Schistosoma mansoni.
    Parasites & vectors, 2015, Aug-13, Volume: 8

    Drug discovery for the neglected tropical disease schistosomiasis has a high priority. Anticancer drugs, especially protein kinase inhibitors, might serve as a starting point for drug discovery owing to the importance of protein kinases in helminth growth and development. Furthermore, the Schistosoma mansoni genome encodes several genes for targets of drugs marketed for human use, including several anticancer drugs.. In this study, we screened the approved oncology drug set of the National Cancer Institute's Developmental Therapeutic Program for antischistosomal activity. Drugs were tested in vitro against the larval and adult stage of S. mansoni. IC50 values and albumin binding were determined for active compounds. Lead compounds were tested in the chronic S. mansoni mouse model.. Eleven of the 114 compounds tested revealed IC50 values ≤ 10 μM against both S. mansoni stages. Five of these lost activity against adult S. mansoni in the presence of serum albumin. Of 6 compounds studied in vivo, the highest activity was observed from two kinase inhibitors trametinib, and vandetanib, which reduced worm burden by 63.6 and 48.1% respectively, after a single oral dose of 400 mg/kg body weight.. Our study has confirmed that oncology drugs possess antischistosomal activity. There is space for further investigation, including elucidation of the mechanisms of action of schistosome-active cancer drugs, application of different treatment courses, and structure-activity relationship studies for improving drug potency.

    Topics: Animals; Antineoplastic Agents; Drug Repositioning; Inhibitory Concentration 50; Mice; Piperidines; Pyridones; Pyrimidinones; Quinazolines; Schistosoma mansoni; Schistosomiasis mansoni; Schistosomicides

2015
Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer.
    Oncology reports, 2015, Volume: 34, Issue:5

    Multikinase inhibitors (MKIs) targeting VEGF receptors and other receptor tyrosine kinases have shown considerable activity in clinical trials of thyroid cancer. Thyroid cancer frequently exhibits activation of the RAS/RAF/MEK/ERK pathway. In other types of cancer, paradoxical ERK activation has emerged as a potential resistance mechanism to RAF-inhibiting drugs including MKIs such as sorafenib and pazopanib. We therefore queried whether the MEK inhibitor trametinib, could augment the activity of pazopanib in thyroid cancer cell lines. Trametinib potently inhibited growth in vitro (GI50 1.1-4.8 nM), whereas pazopanib had more limited in vitro activity, as anticipated (GI50 1.4-7.1 µM). We observed progressive upregulation of ERK activity with pazopanib treatment, an effect abrogated by trametinib. For xenografts (bearing either KRASG12R or BRAFV600E mutations), the combination of trametinib and pazopanib led to sustained shrinkage in tumor volume by 50% or more, compared to pre-treatment baseline. Trametinib also was highly effective as a single agent, compared to pazopanib alone. These preclinical findings support the evaluation of trametinib, alone or in combination with pazopanib or other kinase inhibitors, in thyroid cancer clinical trials. We highlight the importance of pharmacodynamic assessment of the ERK pathway for patients enrolled in trials involving MKIs.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Indazoles; MAP Kinase Signaling System; Mice, Nude; Pyridones; Pyrimidines; Pyrimidinones; Sulfonamides; Thyroid Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

2015
Evaluation of In Vitro Activity of the Class I PI3K Inhibitor Buparlisib (BKM120) in Pediatric Bone and Soft Tissue Sarcomas.
    PloS one, 2015, Volume: 10, Issue:9

    Pediatric bone and soft tissue sarcomas often display increased Akt phosphorylation through up regulation of insulin-like growth factor (IGF1) signaling. Additionally, Akt signaling has been linked to resistance to IGF1 receptor (IGF1R) and mTOR (mammalian target of rapamycin) inhibitors in sarcoma, further demonstrating the role of Akt in tumor survival. This suggests targeting components of the PI3K/Akt pathway may be an effective therapeutic strategy. Here, we investigated the in vitro activity of the pan-class I PI3K inhibitor buparlisib (BKM120) in pediatric bone and soft tissue sarcomas. Buparlisib inhibited activation of Akt and signaling molecules downstream of mTORC1 (mTOR complex 1) in Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma cell lines. Anti-proliferative effects were observed in both anchorage dependent and independent conditions and apoptosis was induced within 24 hours of drug treatment. Buparlisib demonstrated cytotoxicity as a single agent, but was found to be more effective when used in combination. Synergy was observed when buparlisib was combined with the IGF1R inhibitor NVP-AEW541 and the mTORC1 inhibitor rapamycin. The addition of NVP-AEW541 also further reduced phospho-Akt levels and more potently induced apoptosis compared to buparlisib treatment alone. Additionally, the combination of buparlisib with the MEK1/2 inhibitor trametinib resulted in synergy in sarcoma cell lines possessing MAPK pathway mutations. Taken together, these data indicate buparlisib could be a novel therapy for the treatment of pediatric bone and soft tissue sarcomas.

    Topics: Aminopyridines; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Class I Phosphatidylinositol 3-Kinases; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Humans; Mechanistic Target of Rapamycin Complex 1; Morpholines; Multiprotein Complexes; Mutation; Osteosarcoma; Phosphorylation; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Pyridones; Pyrimidines; Pyrimidinones; Pyrroles; Sarcoma; Signal Transduction; TOR Serine-Threonine Kinases

2015
Relapsing pneumonitis due to two distinct inhibitors of the MAPK/ERK pathway: report of a case.
    BMC cancer, 2015, Oct-19, Volume: 15

    BRAF and MEK are component of the MAPK/ERK pathway and inhibitors of these proteins have significantly improved the outcome of metastatic melanoma. We report for the first time two sequential episodes of pneumonitis presumably induced by trametinib (a MEK inhibitor) and vemurafenib (a BRAF inhibitor) in a 50 year-old man.. While receiving trametinib for a metastatic melanoma, the patient developed non-febrile acute respiratory failure in the context of bilateral ground-glass opacities and sub pleural reticulations on high resolution computed tomography. An excess of lymphocytes was found in the bronchoalveolar lavage fluid. Outcome was favorable after simple drug discontinuation. He subsequently developed a similar clinical-imaging picture 6 months into vemurafenib. A transthoracic lung biopsy disclosed interstitial lymphocytic infiltrate, poorly-formed granulomas with multinucleated giant cells and scattered eosinophils. Outcome was again favorable after simple drug discontinuation.. These two episodes in the same patient suggest that MAPK/ERK inhibitors may cause interstitial lung disease and may exert cross toxicity. This side effect is of particular interest for physicians in charge of patients with melanoma but this drug family is currently under development for several other solid tumors.

    Topics: Bronchoalveolar Lavage Fluid; Humans; Indoles; Male; MAP Kinase Kinase 1; MAP Kinase Signaling System; Melanoma; Middle Aged; Pneumonia; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Recurrence; Sulfonamides; Tomography, X-Ray Computed; Vemurafenib

2015
Hepatic hemorrhage as a consequence of rapid response to combined targeted therapy in metastatic melanoma.
    Journal of surgical oncology, 2015, Volume: 112, Issue:8

    A middle-aged female with metastatic melanoma was found to have hemoperitoneum after starting systemic therapy with the BRAF and MEK inhibitors dabrafenib and trametinib. Etiology proved to be bleeding from a known hepatic metastasis. The patient was managed conservatively and eventually resumed systemic therapy with ongoing response. This case serves to illustrate the possible deleterious effects of rapid tumor response after initiation of targeted systemic therapy in patients with metastatic melanoma.

    Topics: Antineoplastic Agents; Female; Hemoperitoneum; Humans; Imidazoles; Liver Neoplasms; Melanoma; Middle Aged; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms

2015
MEK inhibitor GSK1120212-mediated radiosensitization of pancreatic cancer cells involves inhibition of DNA double-strand break repair pathways.
    Cell cycle (Georgetown, Tex.), 2015, Volume: 14, Issue:23

    Over 90% of pancreatic adenocarcinoma PC express oncogenic mutant KRAS that constitutively activates the Raf-MEK-MAPK pathway conferring resistance to both radiation and chemotherapy. MEK inhibitors have shown promising anti-tumor responses in recent preclinical and clinical studies, and are currently being tested in combination with radiation in clinical trials. Here, we have evaluated the radiosensitizing potential of a novel MEK1/2 inhibitor GSK1120212 (GSK212,or trametinib) and evaluated whether MEK1/2 inhibition alters DNA repair mechanisms in multiple PC cell lines.. Radiosensitization and DNA double-strand break (DSB) repair were evaluated by clonogenic assays, comet assay, nuclear foci formation (γH2AX, DNA-PK, 53BP1, BRCA1, and RAD51), and by functional GFP-reporter assays for homologous recombination (HR) and non-homologous end-joining (NHEJ). Expression and activation of DNA repair proteins were measured by immunoblotting.. GSK212 blocked ERK1/2 activity and radiosensitized multiple KRAS mutant PC cell lines. Prolonged pre-treatment with GSK212 for 24-48 hours was required to observe significant radiosensitization. GSK212 treatment resulted in delayed resolution of DNA damage by comet assays and persistent γH2AX nuclear foci. GSK212 treatment also resulted in altered BRCA1, RAD51, DNA-PK, and 53BP1 nuclear foci appearance and resolution after radiation. Using functional reporters, GSK212 caused repression of both HR and NHEJ repair activity. Moreover, GSK212 suppressed the expression and activation of a number of DSB repair pathway intermediates including BRCA1, DNA-PK, RAD51, RRM2, and Chk-1.. GSK212 confers radiosensitization to KRAS-driven PC cells by suppressing major DNA-DSB repair pathways. These data provide support for the combination of MEK1/2 inhibition and radiation in the treatment of PC.

    Topics: Adenocarcinoma; Antineoplastic Agents; Cell Line, Tumor; DNA Breaks, Double-Stranded; DNA Repair; Gene Expression Regulation, Neoplastic; Humans; MAP Kinase Signaling System; Pancreatic Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Radiation Tolerance

2015
Trametinib and dactolisib but not regorafenib exert antiproliferative effects on rat pancreatic stellate cells.
    Hepatobiliary & pancreatic diseases international : HBPD INT, 2015, Volume: 14, Issue:6

    Modulation of the stroma response is considered a promising approach for the treatment of chronic pancreatitis and pancreatic cancer. The aim of this study was to evaluate the effects of three clinically available small molecule kinase inhibitors, regorafenib, trametinib and dactolisib, on effector functions of activated pancreatic stellate cells (PSCs), which play a key role in pancreatic fibrosis.. Cultured rat PSCs were exposed to small molecule kinase inhibitors. Proliferation and cell death were assessed by measuring the incorporation of 5-bromo-2'-deoxyuridine and cytotoxicity, respectively. Levels of mRNA were determined by real-time PCR, while protein expression and phosphorylation were analyzed by immunoblotting. Interleukin-6 levels in culture supernatants were quantified by ELISA. Zymography assays were performed to monitor collagenase activity in culture supernatants.. The MEK inhibitor trametinib and the dual phosphatidylinositol 3-kinase/mTOR inhibitor dactolisib, but not the multi-kinase inhibitor regorafenib, efficiently inhibited PSC proliferation. Trametinib as well as regorafenib suppressed the expression of two autocrine mediators of PSC activation, interleukin-6 and transforming growth factor-beta1. Dactolisib-treated cells expressed less alpha1 type I collagen and lower levels of alpha-smooth muscle actin, a marker of the myofibroblastic PSC phenotype. Simultaneous application of dactolisib and trametinib displayed additive inhibitory effects on cell growth without statistically significant cytotoxicity. Activity of matrix metalloproteinase-2 was not affected by any of the drugs.. We suggest the combination of two drugs, that specifically target two key signaling pathways in PSC, Ras-Raf-MEK-ERK (trametinib) and phosphatidylinositol 3-kinase-AKT-mTOR (dactolisib), as a concept to modulate the activation state of the cells in the context of fibrosis.

    Topics: Actins; Animals; Cell Proliferation; Cells, Cultured; Collagen Type I; Collagen Type I, alpha 1 Chain; Dose-Response Relationship, Drug; Fibrosis; Imidazoles; Interleukin-6; Male; Mitogen-Activated Protein Kinase Kinases; Pancreatic Stellate Cells; Pancreatitis, Chronic; Phenylurea Compounds; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Pyridines; Pyridones; Pyrimidinones; Quinolines; Rats, Inbred Lew; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Transforming Growth Factor beta1

2015
Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients.
    European journal of cancer (Oxford, England : 1990), 2014, Volume: 50, Issue:2

    BRAF-mutant melanoma can be successfully treated by BRAF kinase inhibitors (BRAFi) and MEK kinase inhibitors (MEKi). However, the administration of BRAFi followed by MEKi did not generate promising response rate (RR). The purpose of this investigation was to evaluate the time to progression (TTP) with a mitogen-activated protein kinase (MAPK) pathway upstream inhibition strategy in BRAF mutated melanoma patients. BRAF mutation positive metastatic melanoma patients were identified within the Dermatology Cooperative Oncology Group (DeCOG) network and were treated first with a MEKi and upon progression with a selective BRAFi. A total of 23 melanoma patients (six females, 17 males, aged 47-80 years) were retrospectively analysed for TTP. The total median TTP was 8.9 months. The median TTP for MEKi was 4.8 (1.2-23.2) and subsequent for BRAFi 4.5 (1.2-15.7) months, respectively. A higher RR for MEKi (39%, nine partial responses and 0 complete responses) than previously reported was observed. Our analysis suggests that the reversed inhibition of the MAPK pathway is feasible in BRAF mutated melanoma. The median TTP (8.9 months) is close to the promising BRAF- and MEKi combination therapy (median progression-free survival (PFS) 9.4 months). The total treatment duration of the MAPK inhibition when a MEKi is administered first is similar compared to the reversed sequence, but TTP shifts in favour to the MEKi. This approach is feasible with reasonable tolerability. This clinical investigation encourages further studies in prospective clinical trials to define the optimal treatment schedule for the MAPK pathway inhibition and should be accompanied by molecular monitoring using repeated biopsies.

    Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Disease Progression; Disease-Free Survival; Feasibility Studies; Female; Humans; Imidazoles; Indoles; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mitogen-Activated Protein Kinases; Mutation; Outcome Assessment, Health Care; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Sulfonamides; Time Factors; Vemurafenib

2014
Acneiform eruptions: a common cutaneous toxicity of the MEK inhibitor trametinib.
    The Australasian journal of dermatology, 2014, Volume: 55, Issue:4

    The MEK inhibitor trametinib is currently undergoing clinical trials as the treatment of metastatic melanoma both alone and in combination with the BRAF inhibitor dabrafenib. One of the most frequent side-effects associated with its use as a single agent is the development of acneiform eruptions. These eruptions seem to be reduced when dosed in combination with dabrafenib.. To investigate the prevalence of acneiform eruptions in patients taking the MEK inhibitor trametinib, both alone and in combination with dabrafenib.. All patients enrolled in the trametinib alone (n = 13) or trametinib and dabrafenib combination (n = 30) clinical trials at a single site underwent a retrospective file review. The development and management of acne or acneiform eruptions was noted.. In total, 77% of the trametinib group developed an acneiform eruption on the trial, while only 10% developed acneiform lesions in the combination trial. The patients were treated with oral doxycycline, topical antibiotics or topical antiseptic washes, with a good response. However the condition recurred if these treatments were ceased and the patient was still on trametinib therapy.. The MEK inhibitor trametinib is associated with the development of acneiform eruptions. When combined with dabrafenib the frequency of this side-effect is reduced.

    Topics: Acneiform Eruptions; Administration, Cutaneous; Adult; Aged; Anti-Bacterial Agents; Anti-Infective Agents, Local; Antineoplastic Combined Chemotherapy Protocols; Clindamycin; Clinical Trials as Topic; Doxycycline; Drug Eruptions; Female; Humans; Imidazoles; Male; Melanoma; Middle Aged; Oximes; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Triclosan

2014
COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors.
    Molecular oncology, 2014, Volume: 8, Issue:2

    Keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cuSCCs) develop in 15-30% of patients with BRAF(V600E) metastatic melanoma treated with BRAF inhibitors (BRAFi). These lesions resemble mouse skin tumors induced by the two-stage DMBA/TPA skin carcinogenesis protocol; in this protocol BRAFi accelerates tumor induction. Since prior studies demonstrated cyclooxygenase 2 (COX-2) is necessary for DMBA/TPA tumor induction, we hypothesized that COX-2 inhibition might prevent BRAFi-accelerated skin tumors. Celecoxib, a COX-2 inhibitor, significantly delayed tumor acceleration by the BRAFi inhibitor PLX7420 and decreased tumor number by 90%. Tumor gene expression profiling demonstrated that celecoxib partially reversed the PLX4720-induced gene signature. In PDV cuSCC cells, vemurafenib (a clinically approved BRAFi) increased ERK phosphorylation and soft agar colony formation; both responses were greatly decreased by celecoxib. In clinical trials trametinib, a MEK inhibitor (MEKi) increases BRAFi therapy efficacy in BRAF(V600E) melanomas and reduces BRAFi-induced KA and cuSCC frequency. Trametinib also reduced vemurafenib-induced PDV soft agar colonies, but less efficiently than celecoxib. The trametinb/celecoxib combination was more effective than either inhibitor alone. In conclusion, celecoxib suppressed both BRAFi-accelerated skin tumors and soft-agar colonies, warranting its testing as a chemopreventive agent for non-melanoma skin lesions in patients treated with BRAFi alone or in combination with MEKi.

    Topics: Animals; Carcinoma, Squamous Cell; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Female; Gene Expression Regulation, Neoplastic; Humans; Indoles; Keratoacanthoma; Melanoma; Mice; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyrazoles; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

2014
Cutaneous granulomatous eruption and successful response to potent topical steroids in patients undergoing targeted BRAF inhibitor treatment for metastatic melanoma.
    JAMA dermatology, 2014, Volume: 150, Issue:3

    Targeted BRAF inhibitor therapy (vemurafenib, dabrafenib) is an effective, novel treatment for patients with metastatic melanoma with the V600E BRAF mutation. This therapy is associated with squamous cell carcinomas and keratoacanthomas. Granulomatous eruptions have not been previously reported.. Two patients with melanoma developed cutaneous granulomatous eruptions during targeted BRAF inhibitor therapy. In case 1, after 2 months of treatment with dabrafenib and trametinib (MEK inhibitor), a papular eruption concerning for progression of disease prompted cessation of treatment. After the histopathologic diagnosis of granulomas, the patient was treated with clobetasol ointment with resolution within days and resumption of therapy. In case 2, after 5 months of vemurafenib treatment, the patient developed a granulomatous eruption, which resolved 3 weeks after cessation of therapy.. We report 2 cases of cutaneous granulomatous eruptions on treatment with targeted BRAF inhibitors, a previously unreported association. Although additional investigations are necessary to better elucidate the pathogenic mechanisms, our report includes a treatment plan that prevents unnecessary discontinuation of therapy. Given the Food and Drug Administration approval of vemurafenib for metastatic melanoma, clinicians should be aware of this possible cutaneous reaction and treatment option to optimize patient management.

    Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Biopsy, Needle; Clobetasol; Disease Progression; Drug Eruptions; Female; Follow-Up Studies; Humans; Imidazoles; Immunohistochemistry; Lower Extremity; Male; Melanoma; Molecular Targeted Therapy; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Risk Assessment; Sampling Studies; Sentinel Lymph Node Biopsy; Skin Neoplasms; Survival Rate; Treatment Outcome

2014
Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer.
    Cancer discovery, 2014, Volume: 4, Issue:5

    Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase-activating protein encoded by the NF1 gene. Erlotinib failed to fully inhibit RAS-ERK signaling when neurofibromin levels were reduced. Treatment of neurofibromin-deficient lung cancers with a MAP-ERK kinase (MEK) inhibitor restored sensitivity to erlotinib. Low levels of NF1 expression were associated with primary and acquired resistance of lung adenocarcinomas to EGFR TKIs in patients. These findings identify a subgroup of patients with EGFR-mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors.

    Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mice; Neoplasms, Experimental; Neurofibromin 1; Pyridones; Pyrimidinones

2014
Dabrafenib and trametinib, alone and in combination for BRAF-mutant metastatic melanoma.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2014, Apr-15, Volume: 20, Issue:8

    Dabrafenib and trametinib were approved for use as monotherapies in BRAF-mutant metastatic melanoma by the U.S. Food and Drug Administration (FDA) in 2013, and most recently, their use in combination has received accelerated FDA approval. Both drugs target the mitogen-activated protein kinase (MAPK) pathway: dabrafenib selectively inhibits mutant BRAF that constitutively activates the pathway, and trametinib selectively inhibits MEK1 and MEK2 proteins activated by RAF kinases. The phase III study of dabrafenib in BRAF(V600E) metastatic melanoma reported rapid tumor regression in most patients and a 59% objective RECIST response rate. The median progression-free survival (PFS) and overall survival (OS) were improved compared with dacarbazine. Toxicities were well tolerated and different from those reported for vemurafenib, the first FDA-approved BRAF inhibitor. Efficacy has been demonstrated in other BRAF-mutant genotypes. The phase III study of trametinib in BRAF inhibitor-naïve patients with BRAF(V600E) or BRAF(V600K) also showed benefit with a prolonged median PFS and OS compared with chemotherapy. Trametinib is ineffective in patients who have progressed on BRAF inhibitors. A phase II trial of combined dabrafenib and trametinib demonstrated higher response rates and longer median PFS than dabrafenib monotherapy, with less cutaneous toxicity. Here, we review the clinical development of both drugs as monotherapies and in combination, and discuss their role in the management of BRAF-mutant melanoma.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Exanthema; Fatigue; Humans; Imidazoles; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome

2014
Combination therapy approved for melanoma.
    Cancer discovery, 2014, Volume: 4, Issue:3

    The U.S. Food and Drug Administration approved the use of trametinib and dabrafenib in combination for patients with metastatic or unresectable melanoma with BRAF V600K or V600E mutations-the first combination therapy approved for the disease.

    Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Molecular Targeted Therapy; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Treatment Outcome; United States; United States Food and Drug Administration

2014
Molecular pathways: adaptive kinome reprogramming in response to targeted inhibition of the BRAF-MEK-ERK pathway in cancer.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2014, May-15, Volume: 20, Issue:10

    The central role of the BRAF-MEK-ERK pathway in controlling cell fate has made this pathway a primary target for deregulated activation in cancer. BRaf is activated by Ras proteins allowing Ras oncogenes to constitutively activate the pathway. Activating BRaf mutations are also frequent in several cancers, being the most common oncogenic mutation in thyroid carcinoma and melanoma. There are currently two inhibitors, vemurafenib and dabrafenib, approved for treatment of malignant melanoma having activating BRaf mutations. Concurrent administration of BRAF and MAP-ERK kinase (MEK) inhibitor (trametinib) is significantly more active in patients with BRAF-mutant melanoma than either single agent alone, but progression to resistance ultimately occurs by different mechanisms that increase the activation of extracellular signal-regulated kinase (ERK). Such adaptive changes in tumor cell signaling networks allow bypass of targeted oncoprotein inhibition. This is true with targeted inhibitors for BRaf and MEK as well as specific inhibitors for AKT, mTOR, and many receptor tyrosine kinases such as EGF receptor (EGFR) and HER2. It is this adaptive response to targeted kinase inhibitors that contributes to the failure of single-agent kinase inhibitors to have durable responses. This failure is seen in virtually all cancers treated with single-agent kinase inhibitors, most of which are not as dependent on a single signaling pathway such as BRaf-MEK-ERK in melanoma. Thus, understanding the breadth of adaptive reprogramming responses to specific targeted kinase inhibition will be critical to develop appropriate combination therapies for durable clinical responses.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Extracellular Signal-Regulated MAP Kinases; Humans; Imidazoles; Indoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Melanoma; Models, Biological; Mutation; Neoplasms; Oximes; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2014
BRAFV600E mutation status of involuting and stable nevi in dabrafenib therapy with or without trametinib.
    JAMA dermatology, 2014, Volume: 150, Issue:10

    Recent advances in targeting BRAFV600E mutations, which occur in roughly 50% of melanomas and 70% of benign nevi, have improved response rates and survival in patients with melanoma. With increased survival, the importance of other comorbidities increases and requires consideration in long-term management. This case report discusses dynamic dermoscopic nevus changes that occur during dabrafenib therapy and offers some conclusions regarding BRAF mutations and the changes.. A man in his 30s had been monitored with whole-body dermoscopy at roughly 7-month intervals as part of a nevus surveillance study. Fourteen months after his initial visit, metastases were found, and the patient entered a clinical trial of dabrafenib with or without trametinib therapy. Continued dermoscopic monitoring for the next 12 months revealed that approximately 50% of the existing acquired melanocytic nevi involuted, while the remaining nevi did not change. Biopsy findings from 1 unchanged and 1 involuted nevus showed BRAF wild type in the unchanged nevus, BRAFV600E mutation in the involuting nevus, and no malignant histopathologic characteristics in either one.. Our observations indicate that a previously suggested hypothesis regarding involuting nevi in BRAF inhibitor therapy is correct: Nevi that involute while a patient is undergoing BRAF V600E inhibitor therapy possess the BRAF V600E mutation, while others that grow or remain unchanged are wild type. However larger-scale trials are required to gather conclusive data and create a more complete clinical picture.

    Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Dermoscopy; Humans; Imidazoles; Male; Melanoma; Mutation; Nevus; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms

2014
Effects of AKT inhibitor therapy in response and resistance to BRAF inhibition in melanoma.
    Molecular cancer, 2014, Apr-16, Volume: 13

    The clinical use of BRAF inhibitors for treatment of metastatic melanoma is limited by the development of drug resistance. In this study we investigated whether co-targeting the MAPK and the PI3K-AKT pathway can prevent emergence of resistance or provide additional growth inhibitory effects in vitro.. Anti-tumor effects of the combination of the BRAF inhibitor (BRAFi) dabrafenib and GSK2141795B (AKTi) in a panel of 23 BRAF mutated melanoma cell lines were evaluated on growth inhibition by an ATP-based luminescent assay, on cell cycle and apoptosis by flow cytometry and on cell signaling by western blot. Moreover, we investigated the possibilities of delaying or reversing resistance or achieving further growth inhibition by combining AKTi with dabrafenib and/or the MEK inhibitor (MEKi) trametinib by using long term cultures.. More than 40% of the cell lines, including PTEN-/- and AKT mutants showed sensitivity to AKTi (IC50 < 1.5 μM). The combination of dabrafenib and AKTi synergistically potentiated growth inhibition in the majority of cell lines with IC50 > 5 nM dabrafenib. Combinatorial treatment induced apoptosis only in cell lines sensitive to AKTi. In long term cultures of a PTEN-/- cell line, combinatorial treatment with the MAPK inhibitors, dabrafenib and trametinib, and AKTi markedly delayed the emergence of drug resistance. Moreover, combining AKTi with the MAPK inhibitors from the beginning provided superior growth inhibitory effects compared to addition of AKTi upon development of resistance to MAPK inhibitors in this particular cell line.. AKTi combined with BRAFi-based therapy may benefit patients with tumors harboring BRAF mutations and particularly PTEN deletions or AKT mutations.

    Topics: Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Imidazoles; MAP Kinase Kinase Kinases; Melanoma; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Signal Transduction; Xenograft Model Antitumor Assays

2014
Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors.
    Cancer cell, 2014, May-12, Volume: 25, Issue:5

    MEK inhibitors are clinically active in BRAF(V600E) melanomas but only marginally so in KRAS mutant tumors. Here, we found that MEK inhibitors suppress ERK signaling more potently in BRAF(V600E), than in KRAS mutant tumors. To understand this, we performed an RNAi screen in a KRAS mutant model and found that CRAF knockdown enhanced MEK inhibition. MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAF(V600E). MEK inhibitors induced RAF-MEK complexes in KRAS mutant models, and disrupting such complexes enhanced inhibition of CRAF-dependent ERK signaling. Newer MEK inhibitors target MEK catalytic activity and also impair its reactivation by CRAF, either by disrupting RAF-MEK complexes or by interacting with Ser 222 to prevent MEK phosphorylation by RAF.

    Topics: Animals; Benzamides; Cell Line; Coumarins; Diphenylamine; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; HEK293 Cells; Humans; Indoles; MAP Kinase Kinase 1; MAP Kinase Signaling System; Melanoma; Mice; Mice, Nude; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; raf Kinases; ras Proteins; RNA Interference; RNA, Small Interfering; Sulfonamides; Surface Plasmon Resonance; TNF Receptor-Associated Factor 3; Vemurafenib

2014
MEK inhibition, alone or in combination with BRAF inhibition, affects multiple functions of isolated normal human lymphocytes and dendritic cells.
    Cancer immunology research, 2014, Volume: 2, Issue:4

    Combination therapy with BRAF and MEK inhibition is currently in clinical development for the treatment of BRAF-mutated malignant melanoma. BRAF inhibitors are associated with enhanced antigen-specific T-lymphocyte recognition in vivo. Consequently, BRAF inhibition has been proposed as proimmunogenic and there has been considerable enthusiasm for combining BRAF inhibition with immunotherapy. MEK inhibitors inhibit ERK phosphorylation regardless of BRAF mutational status and have been reported to impair T-lymphocyte and modulate dendritic cell function. In this study, we investigate the effects on isolated T lymphocytes and monocyte-derived dendritic cells (moDC) of a MEK (trametinib) and BRAF (dabrafenib) inhibitor combination currently being evaluated in a randomized controlled clinical trial. The effects of dabrafenib and trametinib, alone and in combination, were studied on isolated normal T lymphocytes and moDCs. Lymphocyte viability, together with functional assays including proliferation, cytokine production, and antigen-specific expansion, were assessed. MoDC phenotype in response to lipopolysaccharide stimulation was evaluated by flow cytometry, as were effects on antigen cross-presentation. Dabrafenib did not have an impact on T lymphocytes or moDCs, whereas trametinib alone or in combination with dabrafenib suppressed T-lymphocyte proliferation, cytokine production, and antigen-specific expansion. However, no significant decrease in CD4(+) or CD8(+) T-lymphocyte viability was observed following kinase inhibition. MoDC cross-presentation was suppressed in association with enhanced maturation following combined inhibition of MEK and BRAF. The results of this study demonstrate that MEK inhibition, alone or in combination with BRAF inhibition, can modulate immune cell function, and further studies in vivo will be required to evaluate the potential clinical impact of these findings.

    Topics: Antigens, Neoplasm; Cell Differentiation; Cell Proliferation; Cross-Priming; Cytokines; Dendritic Cells; Epitopes, T-Lymphocyte; Humans; Imidazoles; Lipopolysaccharides; Lymphocyte Activation; Lymphocyte Subsets; Lymphocytes; Mitogen-Activated Protein Kinase Kinases; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2014
Efficacy of vemurafenib in a trametinib-resistant stage IV melanoma patient--letter.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2014, May-01, Volume: 20, Issue:9

    Topics: Adult; Antineoplastic Agents; Drug Resistance, Neoplasm; Fatal Outcome; Humans; Indoles; Male; Melanoma; Neoplasm Staging; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Treatment Outcome; Vemurafenib

2014
Factors influencing the CNS distribution of a novel MEK-1/2 inhibitor: implications for combination therapy for melanoma brain metastases.
    Drug metabolism and disposition: the biological fate of chemicals, 2014, Volume: 42, Issue:8

    Brain metastases are a major cause of mortality in patients with advanced melanoma. Adequate brain distribution of targeted agents for melanoma will be critical for treatment success. Recently, improvement in overall survival led to US Food and Drug Administration (FDA) approval of the v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, vemurafenib and dabrafenib, and the mitogen-activated protein kinase kinase-1 (MEK)-1/2 inhibitor, trametinib. However, brain metastases and emergence of resistance remain a significant problem. MEK-1/2 is downstream of BRAF in the mitogen-activated protein kinase (MAPK) signaling pathway, making it an attractive target to combat resistance. The recently approved combination of dabrafenib and trametinib has shown improvement in progression-free survival; however, adequate brain distribution of both compounds is required to effectively treat brain metastases. In previous studies, we found limited brain distribution of dabrafenib. The purpose of the current study was to investigate factors influencing the brain distribution of trametinib. In vitro studies indicated that trametinib is a substrate for both P-glycoprotein (P-gp) and Bcrp, efflux transporters found at the blood-brain barrier. In vivo studies in transgenic mouse models confirmed that P-gp plays an important role in restricting brain distribution of trametinib. The brain-to-plasma partition coefficient (AUCbrain/AUCplasma) was approximately 5-fold higher in Mdr1a/b((-/-)) (P-gp knockout) and Mdr1a/b((-/-))Bcrp1((-/-)) (triple knockout) mice when compared with wild-type and Bcrp1((-/-)) (Bcrp knockout) mice. The brain distribution of trametinib was similar between the wild-type and Bcrp knockout mice. These results show that P-gp plays an important role in limiting brain distribution of trametinib and may have important implications for use of trametinib as single agent or in combination therapy for treatment of melanoma brain metastases.

    Topics: Animals; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Transporters; Biological Transport; Blood-Brain Barrier; Brain Neoplasms; Combined Modality Therapy; Dogs; Madin Darby Canine Kidney Cells; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Mice; Mice, Knockout; Mice, Transgenic; Plasma; Protein Kinase Inhibitors; Pyridones; Pyrimidinones

2014
Panniculitis in patients treated with BRAF inhibitors: a case series.
    The American Journal of dermatopathology, 2014, Volume: 36, Issue:6

    Panniculitis is a rare complication of BRAF inhibitor therapy that is used to treat patients with BRAF-mutated metastatic melanoma. We present a clinicopathologic review of 9 patients who developed panniculitis while on BRAF inhibitor therapy. In 13% of patients on vemurafenib, 3% of patients on dabrafenib and 10% on combination of dabrafenib + trametinib, tender erythematous nodular lesions of panniculitis appeared on legs, arms and trunk. Histological evaluation of 8 biopsies from 7 patients showed predominantly neutrophilic infiltrate in 4, lymphocytic in 1, and mixed in 3. Lesions with neutrophilic infiltrate appeared in earlier stages of treatment than those with mixed or lymphocytic infiltrate. All biopsies showed lobular involvement and 5 also had a septal component. In addition, 1 biopsy had lichenoid inflammation in the epidermis and the other had evidence of vasculitis. Most patients responded to conservative medical management without the need to reduce or to stop BRAF inhibitor therapy. Panniculitis seems to be a rare class effect of BRAF inhibitors that is predominantly lobular and neutrophilic, although other patterns can be seen.

    Topics: Adult; Aged; Female; Humans; Imidazoles; Indoles; Male; Melanoma; Middle Aged; Oximes; Panniculitis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

2014
A high content clonogenic survival drug screen identifies mek inhibitors as potent radiation sensitizers for KRAS mutant non-small-cell lung cancer.
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2014, Volume: 9, Issue:7

    Traditional clonogenic survival and high throughput colorimetric assays are inadequate as drug screens to identify novel radiation sensitizers. We developed a method that we call the high content clonogenic survival assay (HCSA) that will allow screening of drug libraries to identify candidate radiation sensitizers.. Drug screen using HCSA was done in 96 well plates. After drug treatment, irradiation, and incubation, colonies were stained with crystal violet and imaged on the INCell 6000 (GE Health). Colonies achieving 50 or more cells were enumerated using the INCell Developer image analysis software. A proof-of-principle screen was done on the KRAS mutant lung cancer cell line H460 and a Custom Clinical Collection (146 compounds).. Multiple drugs of the same class were found to be radiation sensitizers and levels of potency seemed to reflect the clinical relevance of these drugs. For instance, several PARP inhibitors were identified as good radiation sensitizers in the HCSA screen. However, there were also a few PARP inhibitors not found to be sensitizing that have either not made it into clinical development, or in the case of BSI-201, was proven to not even be a PARP inhibitor. We discovered that inhibitors of pathways downstream of activated mutant KRAS (PI3K, AKT, mTOR, and MEK1/2) sensitized H460 cells to radiation. Furthermore, the potent MEK1/2 inhibitor tramenitib selectively enhanced radiation effects in KRAS mutant but not wild-type lung cancer cells.. Drug screening for novel radiation sensitizers is feasible using the HCSA approach. This is an enabling technology that will help accelerate the discovery of novel radiosensitizers for clinical testing.

    Topics: Animals; Antineoplastic Agents; Benzamides; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Mice; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Radiation-Sensitizing Agents; ras Proteins; Tumor Stem Cell Assay

2014
Acneiform eruption in a patient with metastatic melanoma after ceasing combination dabrafenib/trametinib therapy.
    Melanoma research, 2014, Volume: 24, Issue:5

    BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) increase survival in BRAF mutant metastatic melanoma patients; however, they induce a well-known spectrum of cutaneous side effects during treatment. Whereas the BRAFi dabrafenib induces cutaneous squamous cell carcinomas and verrucal keratosis, the MEKi trametinib frequently induces acneiform eruptions that are reversible after drug discontinuation. Furthermore, when dabrafenib and trametinib are used in combination, there are fewer cutaneous toxicities. We report a patient with BRAF mutant metastatic melanoma treated with the BRAFi/MEKi combination therapy who developed an acneiform eruption after treatment discontinuation rather than during active therapy. Moreover, the eruption resolved when the combination treatment was reintroduced and recurred after increasing the dose of trametinib. The eruption may be explained by the longer half-life of trametinib (4.5 days) compared with dabrafenib (5.2 h). This is the first case reported with this particular side effect induced after stopping the treatment and could become more frequent as the BRAFi/MEKi combination of drugs is more frequently prescribed.

    Topics: Acneiform Eruptions; Adrenal Cortex Hormones; Adult; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Drug Administration Schedule; Fatal Outcome; Female; Fever; Humans; Imidazoles; Melanoma; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Time Factors; Treatment Outcome

2014
Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma.
    Melanoma research, 2014, Volume: 24, Issue:5

    BRAF and MEK inhibitors are not established treatments for non-V600 mutation-positive metastatic melanoma. We carried out a retrospective analysis of efficacy and safety in four patients with BRAF K601E and one patient with L597Q mutation-positive metastatic melanoma treated with the MEK inhibitor trametinib. Three patients achieved a RECIST partial response, including the patient with an L597Q mutation. Paired biopsies available in one of the five patients showed reduced phospho-ERK signalling and this corresponded to a metabolic response on F-fluorodeoxyglucose-PET scanning. Trametinib toxicity was manageable. Trametinib has antitumour activity in patients with BRAF K601E and L597Q mutation-positive metastatic melanoma.

    Topics: Aged; Antineoplastic Agents; Biopsy; Extracellular Signal-Regulated MAP Kinases; Female; Fluorodeoxyglucose F18; Humans; Male; MAP Kinase Signaling System; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Phosphorylation; Positron-Emission Tomography; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Signal Transduction; Skin Neoplasms; Treatment Outcome

2014
Function-blocking ERBB3 antibody inhibits the adaptive response to RAF inhibitor.
    Cancer research, 2014, Aug-01, Volume: 74, Issue:15

    ERBB3/HER3 expression and signaling are upregulated in mutant BRAF melanoma as an adaptive, prosurvival response to FDA-approved RAF inhibitors. Because compensatory ERBB3 signaling counteracts the effects of RAF inhibitors, cotargeting ERBB3 may increase the efficacy of RAF inhibitors in mutant BRAF models of melanoma. Here, we corroborate this concept by showing that the ERBB3 function-blocking monoclonal antibody huHER3-8 can inhibit neuregulin-1 activation of ERBB3 and downstream signaling in RAF-inhibited melanoma cells. Targeting mutant BRAF in combination with huHER3-8 decreased cell proliferation and increased cell death in vitro, and decreased tumor burden in vivo, compared with targeting either mutant BRAF or ERBB3 alone. Furthermore, the likelihood of a durable tumor response in vivo was increased when huHER3-8 was combined with RAF inhibitor PLX4720. Together, these results offer a preclinical proof of concept for the application of ERBB3-neutralizing antibodies to enhance the efficacy of RAF inhibitors in melanoma to delay or prevent tumor regrowth. As ERBB3 is often upregulated in response to other kinase-targeted therapeutics, these findings may have implications for other cancers as well.

    Topics: Animals; Antibodies, Monoclonal; Cell Growth Processes; Cell Line, Tumor; Cell Survival; Female; Heterografts; Humans; Indoles; Melanoma; Mice; Mice, Nude; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Receptor, ErbB-3; Signal Transduction; Sulfonamides; Vemurafenib

2014
Co-treatment with panitumumab and trastuzumab augments response to the MEK inhibitor trametinib in a patient-derived xenograft model of pancreatic cancer.
    Neoplasia (New York, N.Y.), 2014, Volume: 16, Issue:7

    Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and epidermal growth factor receptor (EGFR) family signaling are drivers of tumorigenesis in pancreatic ductal adenocarcinoma (PDAC). Previous studies have demonstrated that combinatorial treatment of PDAC xenografts with the mitogen-activated protein kinase-extracellular-signal-regulated kinase (ERK) kinase1/2 (MEK1/2) inhibitor trametinib and the dual EGFR/human epidermal growth factor receptor 2 (HER2) inhibitor lapatinib provided more effective inhibition than either treatment alone. In this study, we have used the therapeutic antibodies, panitumumab (specific for EGFR) and trastuzumab (specific for HER2), to probe the role of EGFR and HER2 signaling in the proliferation of patient-derived xenograft (PDX) tumors. We show that dual anti-EGFR and anti-HER2 therapy significantly augmented the growth inhibitory effects of the MEK1/2 inhibitor trametinib in three different PDX tumors. While significant growth inhibition was observed in both KRAS mutant xenograft groups receiving trametinib and dual antibody therapy (tumors 366 and 608), tumor regression was observed in the KRAS wild-type xenografts (tumor 738) treated in the same manner. Dual antibody therapy in conjunction with trametinib was equally or more effective at inhibiting tumor growth and with lower apparent toxicity than trametinib plus lapatinib. Together, these studies provide further support for a role for EGFR and HER2 in pancreatic cancer proliferation and underscore the importance of therapeutic intervention in both the KRAS-rapidly accelerated fibrosarcoma kinase (RAF)-MEK-ERK and EGFR-HER2 pathways to achieve maximal therapeutic efficacy in patients.

    Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Disease Models, Animal; Drug Therapy, Combination; ErbB Receptors; Humans; Male; Mitogen-Activated Protein Kinases; Mutation; Pancreatic Neoplasms; Panitumumab; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; Receptor, ErbB-2; Signal Transduction; Trastuzumab; Tumor Burden; Xenograft Model Antitumor Assays

2014
Relationships between signaling pathway usage and sensitivity to a pathway inhibitor: examination of trametinib responses in cultured breast cancer lines.
    PloS one, 2014, Volume: 9, Issue:8

    Cellular signaling pathways involving mTOR, PI3K and ERK have dominated recent studies of breast cancer biology, and inhibitors of these pathways have formed a focus of numerous clinical trials. We have chosen trametinib, a drug targeting MEK in the ERK pathway, to address two questions. Firstly, does inhibition of a signaling pathway, as measured by protein phosphorylation, predict the antiproliferative activity of trametinib? Secondly, do inhibitors of the mTOR and PI3K pathways synergize with trametinib in their effects on cell proliferation? A panel of 30 human breast cancer cell lines was chosen to include lines that could be classified according to whether they were ER and PR positive, HER2 over-expressing, and "triple negative". Everolimus (targeting mTOR), NVP-BEZ235 and GSK2126458 (both targeting PI3K/mTOR) were chosen for combination experiments. Inhibition of cell proliferation was measured by IC50 values and pathway utilization was measured by phosphorylation of signaling kinases. Overall, no correlation was found between trametinib IC50 values and inhibition of ERK signaling. Inhibition of ERK phosphorylation was observed at trametinib concentrations not affecting proliferation, and sensitivity of cell proliferation to trametinib was found in cell lines with low ERK phosphorylation. Evidence was found for synergy between trametinib and either everolimus, NVP-BEZ235 or GSK2126458, but this was cell line specific. The results have implications for the clinical application of PI3K/mTOR and MEK inhibitors.

    Topics: Antineoplastic Agents; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Everolimus; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Imidazoles; Inhibitory Concentration 50; MAP Kinase Signaling System; MCF-7 Cells; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyridazines; Pyridones; Pyrimidinones; Quinolines; Signal Transduction; Sirolimus; Sulfonamides; TOR Serine-Threonine Kinases

2014
MAP-kinase pathway up or down? Just look at the skin of your patients!
    Melanoma research, 2014, Volume: 24, Issue:5

    Topics: Acneiform Eruptions; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Imidazoles; Indoles; MAP Kinase Kinase Kinases; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Sulfonamides; Vemurafenib

2014
A case of intracranial hemorrhage caused by combined dabrafenib and trametinib therapy for metastatic melanoma.
    The American journal of case reports, 2014, Oct-12, Volume: 15

    Combination therapy with BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib significantly improves progression-free survival of patients with BRAF V600-positive metastatic melanoma, but their use can be associated with life-threatening toxicities. We report the case of a patient receiving dabrafenib and trametinib for metastatic melanoma who developed intracranial hemorrhage while on therapy. Combination therapy with dabrafenib and trametinib improves progression-free survival of patients with BRAF V600-positive metastatic melanoma. Nevertheless, it is associated with an increased incidence and severity of any hemorrhagic event. To the best of our knowledge, this is the first report of intracranial hemorrhage with pathological confirmation.. We present the case of a 48-year-old man with metastatic melanoma of unknown primary site. He had metastases to the right clavicle, brain, liver, adrenal gland, and the right lower quadrant of the abdomen. He progressed on treatment with alpha-interferon. He was found to have a 4.5-cm mass in the left frontotemporal lobe and underwent gross total resection followed by adjuvant CyberKnife stereotactic irradiation. He was subsequently started on ipilimumab. Treatment was stopped due to kidney injury. He was then placed on dabrafenib and trametinib. He returned for follow-up complaining of severe headache and developed an episode of seizure. MRI showed a large area of edema at the left frontal lobe with midline shift. Emergency craniotomy was performed. Intracranial hemorrhage was found intra-operatively. Pathology from surgery did not find tumor cells, reported as organizing hemorrhage and necrosis with surrounding gliosis; immunohistochemistry for S100 and HMB45 were negative.. This case demonstrates the life-threatening adverse effects that can be seen with the newer targeted biological therapies. It is therefore crucial to maintain a high index of suspicion when patients on this combination therapy present with new neurologic symptoms.

    Topics: Antineoplastic Agents; Craniotomy; Diagnosis, Differential; Drug Therapy, Combination; Humans; Imidazoles; Intracranial Hemorrhages; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Oximes; Positron-Emission Tomography; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Tomography, X-Ray Computed

2014
Rapid evolution of combination therapy in melanoma.
    The New England journal of medicine, 2014, Nov-13, Volume: 371, Issue:20

    Topics: Antineoplastic Combined Chemotherapy Protocols; Azetidines; Female; Humans; Imidazoles; Indoles; Male; MAP Kinase Kinase 1; Melanoma; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Vemurafenib

2014
Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma.
    Journal of the American Academy of Dermatology, 2014, Volume: 71, Issue:6

    BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) frequently cause cutaneous adverse events.. We sought to investigate the cutaneous safety profile of BRAFi versus BRAFi and MEKi combination regimens.. We performed a retrospective cohort study, collecting data from 44 patients with melanoma treated either with BRAFi (vemurafenib or dabrafenib) or BRAFi and MEKi combination regimens (vemurafenib + cobimetinib or dabrafenib + trametinib). Patient characteristics, and the occurrence and severity of cutaneous adverse events, are described.. The development of cutaneous adverse events was significantly less frequent (P = .012) and occurred after longer treatment time (P = .025) in patients treated with BRAFi and MEKi combination regimen compared with patients treated with BRAFi monotherapy. Among patients who received both BRAFi and the combination of BRAFi and MEKi at different time points during their treatment course, the development of squamous cell carcinoma or keratoacanthoma was significantly less frequent when they received the combination regimen (P = .008). Patients receiving vemurafenib developed more cutaneous adverse events (P = .001) and in particular more photosensitivity (P = .010) than patients who did not.. There were a limited number of patients.. Combination regimen with BRAFi and MEKi shows fewer cutaneous adverse events and longer cutaneous adverse event-free interval compared with BRAFi monotherapy.

    Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Carcinoma, Squamous Cell; Female; Follow-Up Studies; Humans; Imidazoles; Indoles; Kaplan-Meier Estimate; Male; Melanoma; Middle Aged; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Neoplasms; Sulfonamides; Vemurafenib; Young Adult

2014
Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma.
    Nature communications, 2014, Dec-02, Volume: 5

    One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAF(V600)-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2(C125S), but not the synonymous MEK1(C121S) protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; GTP Phosphohydrolases; Humans; Imidazoles; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Membrane Proteins; Oximes; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Pyridones; Pyrimidinones; rac1 GTP-Binding Protein; Skin Neoplasms

2014
Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma.
    Nature communications, 2014, Dec-15, Volume: 5

    Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.

    Topics: Aminopyridines; Animals; Antineoplastic Agents; Axl Receptor Tyrosine Kinase; Benzamides; Cell Line, Tumor; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Humans; Imatinib Mesylate; Imidazoles; Indoles; Melanoma; Mice; Microphthalmia-Associated Transcription Factor; Oximes; Piperazines; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidines; Pyrimidinones; Receptor Protein-Tyrosine Kinases; Signal Transduction; Skin Neoplasms; Sulfonamides; Vemurafenib; Xenograft Model Antitumor Assays

2014
GSK drug combination approved for advanced melanoma.
    The American journal of managed care, 2014, Volume: 20, Issue:2 Spec No.

    Topics: Antineoplastic Agents; Drug Approval; Drug Therapy, Combination; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; United States; United States Food and Drug Administration

2014
Novel cutaneous effects of combination chemotherapy with BRAF and MEK inhibitors: a report of two cases.
    The British journal of dermatology, 2013, Volume: 169, Issue:1

    The discovery that some melanoma tumours harbour mutations in the BRAF gene (e.g. V600E) and the subsequent development of specific BRAF inhibitors have greatly improved the treatment of metastatic melanoma. Resistance of tumour cells to BRAF inhibitors is reduced by the addition of an MEK inhibitor; both BRAF and MEK inhibitors have been reported to produce a variety of dermatological toxic effects. Benign naevi often harbour BRAF mutations but few reports exist that document the response of naevus cells to BRAF inhibition. We report sarcoidal-type granulomatous inflammation in two patients with metastatic melanoma undergoing treatment with combination BRAF and MEK inhibitor therapy. This inflammation manifested in one patient as a nonspecific papular eruption; in the other, in association with clinical regression of multiple benign-appearing naevi during the course of therapy. The significance of sarcoidal-type inflammation occurring during treatment of metastatic melanoma with a combination of BRAF and MEK inhibitors is unclear. Its association with the clinical regression of benign-appearing naevi suggests a possible exaggerated inflammatory response to degenerating naevus cells in these lesions.

    Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Head and Neck Neoplasms; Humans; Imidazoles; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Scalp; Skin Neoplasms

2013
Novel MEK inhibitor trametinib and other retinoblastoma gene (RB)-reactivating agents enhance efficacy of 5-fluorouracil on human colon cancer cells.
    Cancer science, 2013, Volume: 104, Issue:6

    Chemotherapy for colorectal cancer has become more complicated and diversified with the appearance of molecular-targeting agents. 5-Fluorouracil (5-FU) has been a mainstay of chemotherapy for colorectal cancer, but it is still unknown whether the combining of 5-FU with novel molecular-targeting agents is effective. Thymidylate synthase (TS) is a direct target of 5-FU, and the low TS level has been generally supposed to sensitize 5-FU's efficacy. We therefore hypothesized that RB-reactivating agents could enhance the efficacy of 5-FU, because the RB-reactivating agents could suppress the function of transcription factor E2F of TS gene promoter. We used three RB-reactivating agents, trametinib/GSK1120212 (MEK inhibitor), fenofibrate (PPARα agonist), and LY294002 (PI3K inhibitor), with 5-FU against human colon cancer HT-29 and HCT15 cells. Trametinib induced p15 and p27 expression and reduced cyclin D1 levels in HT-29 cells. Fenofibrate also dephosphorlated ERK1/2 and reduced cyclin D1 levels in HT-29 cells. LY294002 induced p27 expression in HCT15 cells. All three agents caused dephosphorylation of RB protein and G1-phase arrest with a reduction of TS expression. As a consequence, the combination of 5-FU with each of the agents resulted in a significant decrease of colony numbers in HT-29 or HCT15 cells. These results suggest "RB-reactivation therapy" using molecular-targeting agents to be a new strategy for 5-FU-based chemotherapy. In particular, we strongly expect trametinib, which was discovered in Japan and was recently submitted to FDA for approval, to be used together with established regimens for colorectal cancer.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Cell Cycle; Cell Line, Tumor; Colonic Neoplasms; Enzyme Inhibitors; Fluorouracil; Genes, Retinoblastoma; HT29 Cells; Humans; MAP Kinase Kinase Kinases; Pyridones; Pyrimidinones; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Thymidylate Synthase

2013
Inhibition of the growth of patient-derived pancreatic cancer xenografts with the MEK inhibitor trametinib is augmented by combined treatment with the epidermal growth factor receptor/HER2 inhibitor lapatinib.
    Neoplasia (New York, N.Y.), 2013, Volume: 15, Issue:2

    Mutations of the oncogene KRAS are important drivers of pancreatic cancer progression. Activation of epidermal growth factor receptor (EGFR) and human EGFR2 (HER2) is observed frequent in pancreatic adenocarcinomas. Because of co-activation of these two signaling pathways, we assessed the efficacy of inhibition of EGFR/HER2 receptors and the downstream KRAS effector, mitogen-activated protein kinase/extracellular-signal regulated kinase (ERK) kinase 1 and 2 (MEK1/2), on pancreatic cancer proliferation in vitro and in a murine orthotopic xenograft model. Treatment of established and patient-derived pancreatic cancer cell lines with the MEK1/2 inhibitor trametinib (GSK1120212) inhibited proliferation, and addition of the EGFR/HER2 inhibitor lapatinib enhanced the inhibition elicited by trametinib in three of eight cell lines. Importantly, in the orthotopic xenograft model, treatment with lapatinib and trametinib resulted in significantly enhanced inhibition of tumor growth relative to trametinib treatment alone in four of five patient-derived tumors tested and was, in all cases, significantly more effective in reducing the size of established tumors than treatment with lapatinib or trametinib alone. Acute treatment of established tumors with trametinib resulted in an increase in AKT2 phosphorylation that was blunted in mice treated with both trametinib and lapatinib. These data indicate that inhibition of the EGFR family receptor signaling may contribute to the effectiveness of MEK1/2 inhibition of tumor growth possibly through the inhibition of feedback activation of receptor tyrosine kinases in response to inhibition of the RAS-RAF-MEK-ERK pathway. These studies provide a rationale for assessing the co-inhibition of these pathways in the treatment of pancreatic cancer patients.

    Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; ErbB Receptors; Humans; Lapatinib; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Neoplasm Transplantation; Pancreatic Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Quinazolines; Receptor, ErbB-2; Signal Transduction

2013
Characteristics of lung cancers harboring NRAS mutations.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2013, May-01, Volume: 19, Issue:9

    We sought to determine the frequency and clinical characteristics of patients with lung cancer harboring NRAS mutations. We used preclinical models to identify targeted therapies likely to be of benefit against NRAS-mutant lung cancer cells.. We reviewed clinical data from patients whose lung cancers were identified at six institutions or reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) to harbor NRAS mutations. Six NRAS-mutant cell lines were screened for sensitivity against inhibitors of multiple kinases (i.e., EGFR, ALK, MET, IGF-1R, BRAF, PI3K, and MEK).. Among 4,562 patients with lung cancers tested, NRAS mutations were present in 30 (0.7%; 95% confidence interval, 0.45%-0.94%); 28 of these had no other driver mutations. 83% had adenocarcinoma histology with no significant differences in gender. While 95% of patients were former or current smokers, smoking-related G:C>T:A transversions were significantly less frequent in NRAS-mutated lung tumors than KRAS-mutant non-small cell lung cancer [NSCLC; NRAS: 13% (4/30), KRAS: 66% (1772/2733), P < 0.00000001]. Five of 6 NRAS-mutant cell lines were sensitive to the MEK inhibitors, selumetinib and trametinib, but not to other inhibitors tested.. NRAS mutations define a distinct subset of lung cancers (∼1%) with potential sensitivity to MEK inhibitors. Although NRAS mutations are more common in current/former smokers, the types of mutations are not those classically associated with smoking.

    Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; DNA Mutational Analysis; Female; Gene Frequency; Genetic Association Studies; GTP Phosphohydrolases; Humans; Inhibitory Concentration 50; Lung Neoplasms; Male; Membrane Proteins; Middle Aged; Mutation, Missense; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; ras Proteins

2013
MicroRNA 9-3p targets β1 integrin to sensitize claudin-low breast cancer cells to MEK inhibition.
    Molecular and cellular biology, 2013, Volume: 33, Issue:11

    MEK1/2 inhibitors such as AZD6244 are in clinical trials for the treatment of multiple cancers, including breast cancer. Targeted kinase inhibition can induce compensatory kinome changes, rendering single therapeutic agents ineffective. To identify target proteins to be used in a combinatorial approach to inhibit tumor cell growth, we used a novel strategy that identified microRNAs (miRNAs) that synergized with AZD6244 to inhibit the viability of the claudin-low breast cancer cell line MDA-MB-231. Screening of a miRNA mimic library revealed the ability of miR-9-3p to significantly enhance AZD6244-induced extracellular signal-regulated kinase inhibition and growth arrest, while miR-9-3p had little effect on growth alone. Promoter methylation of mir-9 genes correlated with low expression of miR-9-3p in different breast cancer cell lines. Consistent with miR-9-3p having synthetic enhancer tumor suppressor characteristics, miR-9-3p expression in combination with MEK inhibitor caused a sustained loss of c-MYC expression and growth inhibition. The β1 integrin gene (ITGB1) was identified as a new miR-9-3p target, and the growth inhibition seen with small interfering RNA knockdown or antibody blocking of ITGB1 in combination with MEK inhibitor phenocopied the growth inhibition seen with miR-9-3p plus AZD6244. The miRNA screen led to identification of a druggable protein, ITGB1, whose functional inhibition synergizes with MEK inhibitor.

    Topics: 3' Untranslated Regions; Benzimidazoles; Breast Neoplasms; Cell Movement; Cell Proliferation; Claudins; Enzyme Inhibitors; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; Integrin beta1; MAP Kinase Kinase Kinases; MicroRNAs; Pyridones; Pyrimidinones

2013
FDA approves two new drugs against advanced melanoma.
    American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 2013, Jul-01, Volume: 70, Issue:13

    Topics: Antineoplastic Agents; Humans; Imidazoles; Melanoma; Neoplasm Staging; Oximes; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome; United States; United States Food and Drug Administration

2013
Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions.
    PloS one, 2013, Volume: 8, Issue:7

    Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAF(V600E) kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAF(V600E)-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor.

    Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Evaluation, Preclinical; Enzyme Activation; Female; Humans; Imidazoles; Melanoma; Mice; Mitogen-Activated Protein Kinases; Mutation; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

2013
Trametinib: first global approval.
    Drugs, 2013, Volume: 73, Issue:11

    Trametinib is an orally bioavailable mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor with antineoplastic activity. The compound specifically binds to MEK1 and MEK2, resulting in inhibition of growth factor-mediated cell signalling and cellular proliferation in various cancers. Originally developed by Japan Tobacco, GlaxoSmithKline has licensed exclusive worldwide rights to the compound and conducted development in a number of different cancer types. Trametinib, as a monotherapy, has been approved in the US for the treatment of unresectable or metastatic malignant melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. The compound, as a monotherapy, has also been submitted for regulatory review in the EU for BRAF mutation-positive malignant melanoma, and is in phase III development in Europe, Argentina, Canada and Oceania. Phase II development is underway for pancreatic cancer, non-small cell lung cancer and relapsed or refractory leukaemias. GlaxoSmithKline is also developing trametinib for use in combination with dabrafenib in BRAF V600 mutation-positive metastatic cutaneous melanoma; the combination is at the preregistration stage in the EU and a phase III clinical programme is underway worldwide. Phase II development for this combination is also underway in colorectal cancer. Several phase I trials have also been initiated to evaluate trametinib in combination with other drugs for the treatment of various solid tumours and haematological malignancies. A paediatric oral solution formulation has been assessed against the oral tablet formulation in a phase I trial. This article summarizes the milestones in the development of trametinib leading to this first approval for unresectable or metastatic BRAF mutation-positive malignant melanoma.

    Topics: Clinical Trials as Topic; Drug Approval; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Melanoma, Cutaneous Malignant; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

2013
TGF-β1 and TNF-α differentially regulate Twist1 mediated resistance towards BRAF/MEK inhibition in melanoma.
    Pigment cell & melanoma research, 2013, Volume: 26, Issue:6

    Resistance to BRAF and MEK inhibition is a common phenomenon in melanoma. Cytokines and transcription factors have been attributed to contribute to the loss of sensitivity towards these inhibitors. Here, we show that transforming growth factor (TGF)-β1 if combined with PLX4032, a BRAF inhibitor, or GSK1120212, a MEK inhibitor, substantially increased cell death in BRAF-mutant melanoma cell lines. This increase was based on the combined regulatory decrease in Twist1, an antiapoptotic protein. Overexpression or silencing of Twist1 attenuated or aggravated induction of apoptosis through PLX4032 or GSK1120212, respectively. Exposure to tumour necrosis factor (TNF)-α, however, led to increased Twist1 levels and oppositional decrease in cell death if exposed to PLX4032 or GSK1120212. This increase in drug resistance again depended on Twist1 levels. Our studies suggest that Twist1 as a common downstream target of multiple signalling cascades plays a crucial role in mediating drug resistance to BRAF- and MEK-targeted molecular inhibitors.

    Topics: Apoptosis; Caspase 3; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Indoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Nuclear Proteins; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Sulfonamides; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Twist-Related Protein 1; Vemurafenib

2013
Dabrafenib (Tafinlar) and trametinib (Mekinist) metastatic melanoma.
    The Medical letter on drugs and therapeutics, 2013, Aug-05, Volume: 55, Issue:1422

    Topics: Antineoplastic Agents; Humans; Imidazoles; Melanoma; Oximes; Pyridones; Pyrimidinones

2013
Melanoma combination therapies ward off tumor resistance.
    Nature biotechnology, 2013, Volume: 31, Issue:8

    Topics: Combined Modality Therapy; Drug Approval; Humans; Imidazoles; Melanoma; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; United States; United States Food and Drug Administration

2013
Trametinib for the treatment of melanoma.
    Drugs of today (Barcelona, Spain : 1998), 2013, Volume: 49, Issue:8

    Advanced melanoma traditionally has had poor prognosis with limited, modestly effective and relatively toxic systemic treatment options like cytotoxic chemotherapy (dacarbazine) and immunomodulating agents (high-dose interleukin-2 and ipilimumab) which have response rates of 6-20%. With the identification of BRAF mutations found to be present in 50% of melanomas and the clinical success of serine/threonine-protein kinase B-raf inhibitors the prognostic landscape of melanoma has changed considerably. Vemurafenib and dabrafenib have been at the forefront of antimelanoma-targeted agents with a tolerable side effect profile and efficacy that compared well with the standard chemotherapy. These characteristics have led to the regulatory approval of both agents for the treatment of melanoma. However, these agents are not curative and have a short life span primarily due to rapidly occurring drug resistance. More recently, mitogen-activated protein kinase kinase (MEK) inhibitors have been found to have strong anticancer activity independently as well as when combined with other agents like B-raf inhibitors due to their activity downstream of RAF. Preclinical data and limited clinical data suggest that MEK inhibitors may be a component of effective therapy for a broad spectrum of cancers with other oncogenic drivers.

    Topics: Animals; Antineoplastic Agents; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Pyridones; Pyrimidinones; Skin Neoplasms

2013
BRAF inhibitor-driven tumor proliferation in a KRAS-mutated colon carcinoma is not overcome by MEK1/2 inhibition.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2013, Dec-10, Volume: 31, Issue:35

    Topics: Cell Proliferation; Colonic Neoplasms; Humans; Imidazoles; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Middle Aged; Mutation; Oximes; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; ras Proteins; Treatment Outcome

2013
Requirement for interaction of PI3-kinase p110α with RAS in lung tumor maintenance.
    Cancer cell, 2013, Nov-11, Volume: 24, Issue:5

    RAS proteins directly activate PI3-kinases. Mice bearing a germline mutation in the RAS binding domain of the p110α subunit of PI3-kinse are resistant to the development of RAS-driven tumors. However, it is unknown whether interaction of RAS with PI3-kinase is required in established tumors. The need for RAS interaction with p110α in the maintenance of mutant Kras-driven lung tumors was explored using an inducible mouse model. In established tumors, removal of the ability of p110α to interact with RAS causes long-term tumor stasis and partial regression. This is a tumor cell-autonomous effect, which is improved significantly by combination with MEK inhibition. Total removal of p110α expression or activity has comparable effects, albeit with greater toxicities.

    Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Hormonal; Class I Phosphatidylinositol 3-Kinases; Disease Progression; Humans; Lung; Lung Neoplasms; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitogen-Activated Protein Kinases; Mutation; Protein Binding; Protein Interaction Domains and Motifs; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidinones; Tamoxifen; Tumor Burden

2013
Cutaneous effects of BRAF inhibitor therapy: a case series.
    Annals of oncology : official journal of the European Society for Medical Oncology, 2013, Volume: 24, Issue:2

    The cutaneous effects of rapidly accelerated fibrosarcoma kinase B (BRAF) inhibitors are not well understood. Squamous cell carcinoma (SCC), keratoacanthoma, and photosensitivity have been described in patients taking BRAF inhibitors.. To characterize the timing and frequency of skin lesions in patients receiving BRAF inhibitor therapy, we utilized a retrospective case review of 53 patients undergoing treatment with BRAF inhibitors for 4-92 weeks of therapy. Patients were evaluated at baseline, and then followed at 4- to 12-week intervals. Charts were retrospectively reviewed, and the morphology and timing of cutaneous events were recorded.. Thirty-three of the 53 charts met exclusion/inclusion criteria, 15 were treated with vemurafenib, and 18 were treated with GSK 2118436/GSK 1120212. Of 33 patients treated with BRAF inhibitor, 13 developed photosensitivity (39.4%), 10 developed actinic keratoses (30.3%), 10 developed warts (30.3%), and 6 developed SCC (18.2%).. Multiple cutaneous findings were observed in the 33 patients taking BRAF inhibitors. The previously described association with SCC and photosensitivity was observed in these patients as well. Over half of the observed SCCs were invasive in nature. Photosensitivity continues to be frequent with BRAF inhibitors. Patients taking BRAF inhibitors should have regular full body skin exams. Further studies are necessary to better elucidate the rates of these adverse cutaneous effects.

    Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Female; Humans; Imidazoles; Indoles; Keratoacanthoma; Keratosis, Actinic; Male; Melanoma; Middle Aged; Neoplasms; Oximes; Photosensitivity Disorders; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Diseases; Sulfonamides; Vemurafenib; Warts

2013
New year, new science.
    Nature, 2013, Jan-03, Volume: 493, Issue:7430

    Topics: Animals; Astronomical Phenomena; Clinical Trials as Topic; Embryonic Stem Cells; Genes; Global Warming; Humans; Intestines; Mental Disorders; Neoplasms; Patents as Topic; Pyridones; Pyrimidinones; Reference Books; Research Report; Research Support as Topic; Retina; Science

2013
BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2013, Mar-01, Volume: 19, Issue:5

    To evaluate the effects of BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma.. Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10 to 14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF + MEK inhibition (dabrafenib + trametinib) and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T-cell markers, and immunomodulatory cytokines.. Treatment with either BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8+ T-cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines [interleukin (IL)-6 and IL-8] and an increase in markers of T-cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 was increased on treatment. A decrease in melanoma antigen expression and CD8 T-cell infiltrate was noted at time of progression on BRAF inhibitor alone and was reversed with combined BRAF and MEK inhibition.. Together, these data suggest that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T-cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma.

    Topics: Apoptosis; Biomarkers, Tumor; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Fluorescent Antibody Technique; Humans; Imidazoles; Indoles; MAP Kinase Kinase 1; Melanoma; Melanoma-Specific Antigens; Neoplasm Staging; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides; Tumor Microenvironment; Vemurafenib

2013
Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212.
    Molecular cancer therapeutics, 2012, Volume: 11, Issue:3

    The MEK1 and MEK2 inhibitor GSK1120212 is currently in phase II/III clinical development. To identify predictive biomarkers, sensitivity to GSK1120212 was profiled for 218 solid tumor cell lines and 81 hematologic malignancy cell lines. For solid tumors, RAF/RAS mutation was a strong predictor of sensitivity. Among RAF/RAS mutant lines, co-occurring PIK3CA/PTEN mutations conferred a cytostatic response instead of a cytotoxic response for colon cancer cells that have the biggest representation of the comutations. Among KRAS mutant cell lines, transcriptomics analysis showed that cell lines with an expression pattern suggestive of epithelial-to-mesenchymal transition were less sensitive to GSK1120212. In addition, a proportion of cell lines from certain tissue types not known to carry frequent RAF/RAS mutations also seemed to be sensitive to GSK1120212. Among these were breast cancer cell lines, with triple negative breast cancer cell lines being more sensitive than cell lines from other breast cancer subtypes. We identified a single gene DUSP6, whose expression was associated with sensitivity to GSK1120212 and lack of expression associated with resistance irrelevant of RAF/RAS status. Among hematologic cell lines, acute myeloid leukemia and chronic myeloid leukemia cell lines were particularly sensitive. Overall, this comprehensive predictive biomarker analysis identified additional efficacy biomarkers for GSK1120212 in RAF/RAS mutant solid tumors and expanded the indication for GSK1120212 to patients who could benefit from this therapy despite the RAF/RAS wild-type status of their tumors.

    Topics: Antineoplastic Agents; Biomarkers, Tumor; Blotting, Western; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Dual Specificity Phosphatase 6; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HeLa Cells; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Molecular Structure; Mutation; Oligonucleotide Array Sequence Analysis; Phosphatidylinositol 3-Kinases; Prognosis; Protein Kinase Inhibitors; PTEN Phosphohydrolase; Pyridones; Pyrimidinones; raf Kinases; ras Proteins; Transcriptome

2012
Suppressive effect of an orally active MEK1/2 inhibitor in two different animal models for rheumatoid arthritis: a comparison with leflunomide.
    Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2012, Volume: 61, Issue:5

    To examine the effects of a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2-inhibitor, JTP-74057, on inflammatory arthritis development, and compare its anti-arthritic effect with leflunomide.. Human, mouse, and rat peripheral blood mononuclear cells (PBMCs) were used. Lewis rats and DBA/1J mice were used for animal models.. JTP-74057 was tested between 0.1-100 nM in in-vitro studies. JTP-74057 (0.01-0.3 mg/kg) and leflunomide (2-10 mg/kg) were administered orally in vivo.. PBMCs were stimulated with lipopolysaccharide. Adjuvant-induced arthritis (AIA) and type II collagen-induced arthritis (CIA) was induced in Lewis rats or DBA1/J mice, respectively.. JTP-74057 blocked tumor necrosis factor-α and interleukin-6 production from PBMCs. AIA and CIA development were suppressed almost completely by 0.1 mg/kg of JTP-74057 or 10 mg/kg of leflunomide. In the CIA, JTP-74057, but not leflunomide, suppressed collagen-reactive T-cell proliferation ex vivo, whereas leflunomide, but not JTP-74057, suppressed anti-collagen antibody production.. JTP-74057 exerts potent anti-arthritic effects with a different profile from leflunomide, suggesting that JTP-74057 may be useful as a new therapeutic reagent in the treatment of rheumatoid arthritis.

    Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Collagen Type II; Cytokines; Enzyme Inhibitors; Humans; Interleukin-6; Isoxazoles; Leflunomide; Lipopolysaccharides; Lymphocyte Activation; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mice; Mice, Inbred ICR; Pyridones; Pyrimidinones; Rats; Rats, Sprague-Dawley

2012
Successful rechallenge in two patients with BRAF-V600-mutant melanoma who experienced previous progression during treatment with a selective BRAF inhibitor.
    Melanoma research, 2012, Volume: 22, Issue:6

    The v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene is mutated at position 600 in about 50% of melanoma. Mutant BRAF activates the downstream effectors of the RAS-RAF-MEK-MAPK pathways and is a driver oncogene in these melanoma cells. Selective BRAF-V600 inhibitors (vemurafenib, dabrafenib) have high antitumor activity against BRAF-V600-mutant melanoma with objective tumor response rates. Resistance, however, develops within less than a year in the majority of patients. Several different mechanisms have been found to mediate acquired resistance, but these do not involve the occurrence of secondary mutations in the BRAF gene. Two patients with BRAF-V600E mutant melanoma who had documented progression during treatment with dabrafenib/GSK1120212 and dabrafenib, respectively, were rechallenged with dabrafenib and vemurafenib after a treatment-free interval of 8 and 4 months during which further progression was documented. Both patients showed a marked clinical response and, in both, objective tumor regression (qualifying as a mixed and a partial response according to RECIST) was documented. These two case observations indicate that resistance to BRAF-selective inhibitors can be reversible following treatment interruption.

    Topics: Adult; Antineoplastic Agents; Disease Progression; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

2012
Promises from trametinib in RAF active tumors.
    The New England journal of medicine, 2012, Jul-12, Volume: 367, Issue:2

    Topics: Antineoplastic Agents; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

2012
Combination small molecule MEK and PI3K inhibition enhances uveal melanoma cell death in a mutant GNAQ- and GNA11-dependent manner.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2012, Aug-15, Volume: 18, Issue:16

    Activating Q209L/P mutations in GNAQ or GNA11 (GNAQ/11) are present in approximately 80% of uveal melanomas. Mutant GNAQ/11 are not currently therapeutically targetable. Inhibiting key down-stream effectors of GNAQ/11 represents a rational therapeutic approach for uveal melanomas that harbor these mutations. The mitogen-activated protein/extracellular signal-regulated kinase/mitogen-activated protein kinase (MEK/MAPK) and PI3K/AKT pathways are activated in uveal melanoma. In this study, we test the effect of the clinically relevant small molecule inhibitors GSK1120212 (MEK inhibitor) and GSK2126458 (pan class I PI3K inhibitor) on uveal melanoma cells with different GNAQ/11 mutation backgrounds.. We use the largest set of genetically annotated uveal melanoma cell lines to date to carry out in vitro cellular signaling, cell-cycle regulation, growth, and apoptosis analyses. RNA interference and small molecule MEK and/or PI3K inhibitor treatment were used to determine the dependency of uveal melanoma cells with different GNAQ/11 mutation backgrounds on MEK/MAPK and/or PI3K/AKT signaling. Proteomic network analysis was done to unveil signaling alterations in response to MEK and/or PI3K small molecule inhibition.. GNAQ/11 mutation status was not a determinant of whether cells would undergo cell-cycle arrest or growth inhibition to MEK and/or phosphoinositide 3-kinase (PI3K) inhibition. A reverse correlation was observed between MAPK and AKT phosphorylation after MEK or PI3K inhibition, respectively. Neither MEK nor PI3K inhibition alone was sufficient to induce apoptosis in the majority of cell lines; however, the combination of MEK + PI3K inhibitor treatment resulted in the marked induction of apoptosis in a GNAQ/11 mutant-dependent manner.. MEK + PI3K inhibition may be an effective combination therapy in uveal melanoma, given the inherent reciprocal activation of these pathways within these cells.

    Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Cell Death; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Silencing; GTP-Binding Protein alpha Subunits; GTP-Binding Protein alpha Subunits, Gq-G11; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyridazines; Pyridones; Pyrimidinones; Quinolines; Signal Transduction; Sulfonamides; Uveal Neoplasms

2012
The coming of age of MEK.
    The Lancet. Oncology, 2012, Volume: 13, Issue:8

    Topics: Antineoplastic Agents; Female; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Melanoma; Neoplasms; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms; Uveal Neoplasms

2012
Identification and characterization of a novel chemotype MEK inhibitor able to alter the phosphorylation state of MEK1/2.
    Oncotarget, 2012, Volume: 3, Issue:12

    A small molecule compound, JTP-74057/GSK1120212/trametinib, had been discovered as a very potent antiproliferative agent able to induce the accumulation of CDK inhibitor p15INK4b. To conduct its drug development rationally as an anticancer agent, molecular targets of this compound were identified as MEK1/2 using compound-affinity chromatography. It was shown that JTP-74057 directly bound to MEK1 and MEK2 and allosterically inhibited their kinase activities, and that its inhibitory characteristics were similar to those of the known and different chemotype of MEK inhibitors PD0325901 and U0126. It was further shown that JTP-74057 induced rapid and sustained dephosphorylation of phosphorylated MEK in HT-29 colon and other cancer cell lines, while this decrease in phosphorylated MEK was not observed in PD0325901-treated cancer cells. Physicochemical analyses revealed that JTP-74057 preferentially binds to unphosphorylated MEK (u-MEK) in unique characteristics of both high affinity based on extremely low dissociation rates and ability stabilizing u-MEK with high thermal shift, which were markedly different from PD0325901. These findings indicate that JTP-74057 is a novel MEK inhibitor able to sustain MEK to be an unphosphorylated form resulting in pronounced suppression of the downstream signaling pathways involved in cellular proliferation.

    Topics: Allosteric Regulation; Antineoplastic Agents; Benzamides; Butadienes; Chromatography, Affinity; Diphenylamine; Dose-Response Relationship, Drug; HEK293 Cells; HT29 Cells; Humans; Kinetics; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Molecular Structure; Molecular Targeted Therapy; Neoplasms; Nitriles; Phosphorylation; Protein Binding; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Signal Transduction

2012
GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition.
    Clinical cancer research : an official journal of the American Association for Cancer Research, 2011, Mar-01, Volume: 17, Issue:5

    Despite their preclinical promise, previous MEK inhibitors have shown little benefit for patients. This likely reflects the narrow therapeutic window for MEK inhibitors due to the essential role of the P42/44 MAPK pathway in many nontumor tissues. GSK1120212 is a potent and selective allosteric inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes with promising antitumor activity in a phase I clinical trial (ASCO 2010). Our studies characterize GSK1120212' enzymatic, cellular, and in vivo activities, describing its unusually long circulating half-life.. Enzymatic studies were conducted to determine GSK1120212 inhibition of recombinant MEK, following or preceding RAF kinase activation. Cellular studies examined GSK1120212 inhibition of ERK1 and 2 phosphorylation (p-ERK1/2) as well as MEK1/2 phosphorylation and activation. Further studies explored the sensitivity of cancer cell lines, and drug pharmacokinetics and efficacy in multiple tumor xenograft models.. In enzymatic and cellular studies, GSK1120212 inhibits MEK1/2 kinase activity and prevents Raf-dependent MEK phosphorylation (S217 for MEK1), producing prolonged p-ERK1/2 inhibition. Potent cell growth inhibition was evident in most tumor lines with mutant BRAF or Ras. In xenografted tumor models, GSK1120212 orally dosed once daily had a long circulating half-life and sustained suppression of p-ERK1/2 for more than 24 hours; GSK1120212 also reduced tumor Ki67, increased p27(Kip1/CDKN1B), and caused tumor growth inhibition in multiple tumor models. The largest antitumor effect was among tumors harboring mutant BRAF or Ras.. GSK1120212 combines high potency, selectivity, and long circulating half-life, offering promise for successfully targeting the narrow therapeutic window anticipated for clinical MEK inhibitors.

    Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p27; Female; Genes, ras; Humans; Immunoblotting; Ki-67 Antigen; MAP Kinase Signaling System; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Neoplasms, Experimental; Phosphorylation; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Rats; Rats, Sprague-Dawley; Xenograft Model Antitumor Assays

2011
Novel agents in the management of pancreatic adenocarcinoma: phase I studies. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011.
    JOP : Journal of the pancreas, 2011, Mar-09, Volume: 12, Issue:2

    Pancreatic adenocarcinoma has repetitively proved refractory to chemotherapy and biologic compounds with only a few drugs offering limited benefit. A number of novel regimens has been tested in phase I trials and reported recently in the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. Specifically, a novel mitogen-activated protein kinase kinase (MEK) inhibitor, a connective tissue growth factor inhibitor, a coagulase factor VIIa inhibitor, as well as adenovirus delivery of herpes simplex virus thymidine synthase gene followed by anti-herpetic treatment have all proven to be safe in pancreatic cancer patients. Phase II trials will provide further evidence whether they can become clinically relevant in the future.

    Topics: Adenocarcinoma; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase I as Topic; Connective Tissue Growth Factor; Deoxycytidine; Enzyme Inhibitors; Factor VIIa; Gemcitabine; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Pancreatic Neoplasms; Pyridones; Pyrimidinones; Treatment Outcome

2011
Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo.
    International journal of oncology, 2011, Volume: 39, Issue:1

    The MAPK pathway is one of the most important pathways for novel anticancer drug development. We performed high-throughput screening for compounds that induce expression of p15INK4b, and identified JTP-74057 (GSK1120212), which is being evaluated in ongoing phase I, II and III clinical trials. We characterized its antitumor activities in vitro and in vivo. JTP-74057 strongly inhibited MEK1/2 kinase activities, but did not inhibit another 98 kinase activities. Treatment by JTP-74057 resulted in growth inhibition accompanied with upregulation of p15INK4b and/or p27KIP1 in most of the colorectal cancer cell lines tested. Daily oral administration of JTP-74057 for 14 days suppressed tumor growth of HT-29 and COLO205 xenografts in nude mice. Notably, tumor regression was observed only in COLO205 xenografts, and COLO205 was much more sensitive to JTP-74057-induced apoptosis than HT-29 in vitro. Treatment with an Akt inhibitor enhanced the JTP-74057-induced apoptosis in HT-29 cells. Finally, JTP-74057 exhibited an additive or a synergistic effect in combination with the standard-of-care agents, 5-fluorouracil, oxaliplatin or SN-38. JTP-74057, a highly specific and potent MEK1/2 inhibitor, exerts favorable antitumor activities in vitro and in vivo. Sensitivity to JTP-74057-induced apoptosis may be an important factor for the estimation of in vivo efficacy, and sensitivity was enhanced by an Akt inhibitor. These results suggest the usefulness of JTP-74057 in therapeutic applications for colorectal cancer patients.

    Topics: Animals; Antimetabolites, Antineoplastic; Apoptosis; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Drug Synergism; Female; Fluorouracil; HCT116 Cells; HT29 Cells; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Xenograft Model Antitumor Assays

2011