binimetinib and Colorectal-Neoplasms

The

Topics: Cetuximab; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Humans; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Proto-Oncogene Proteins B-raf

BRAF V600E mutations are associated with 8-10% of metastatic colorectal cancers (mCRC) and carry a poor prognosis with limited therapeutic options. In contrast to metastatic melanoma, BRAF inhibition alone or in combination with mitogen-activated protein kinase kinase (MEK) inhibitors has shown little utility in the treatment of BRAF V600E-mutant mCRC. This is secondary to upstream activation of the epidermal growth factor receptor (EGFR) pathway and other escape mechanisms. Combining RAF and MEK inhibitors with inhibition of the EGFR pathway through an anti-EGFR receptor antibody (cetuximab) led to the BEACON clinical trial (binimetinib, encorafenib and cetuximab). Trial patients had undergone at least one prior line of chemotherapy. The trial met all its endpoints and is now included in NCCN (National Comprehensive Cancer Network) guidelines. Herein we provide updates in treatment options for patients with BRAF V600E-mutant mCRC, focusing on the practice-changing BEACON-triplet regimen, the first chemotherapy-free combination regimen for mCRC. This combination is being explored frontline in the ANCHOR clinical trial.

Topics: Benzimidazoles; Carbamates; Cetuximab; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Drug Therapy, Combination; Humans; Mutation; Neoplasm Metastasis; Proto-Oncogene Proteins B-raf; Sulfonamides

In the BEACON CRC study (NCT02928224), encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care (control) in patients with BRAF V600E metastatic colorectal cancer (mCRC). Quality of life (QoL) was a secondary endpoint, assessed using validated instruments.. BEACON CRC was a randomized, open-label, phase III study comparing encorafenib plus cetuximab with or without binimetinib and the investigator's choice of irinotecan plus cetuximab or FOLFIRI plus cetuximab (chemotherapy control) in patients with previously treated BRAF V600E mCRC. Patient-reported QoL assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC) and Functional Assessment of Cancer Therapy-Colorectal (FACT-C). The primary outcome for these tools was time to definitive 10% deterioration.. Encorafenib plus cetuximab, both with and without binimetinib, was associated with longer median times to definitive 10% deterioration versus the control group in the EORTC Global Health Status scale [HR (95% CI): 0.65 (0.52-0.80) versus 0.61 (0.49-0.75), respectively] and the FACT-C functional well-being subscale [HR (95% CI): 0.62 (0.50-0.76) versus 0.58 (0.47-0.72), respectively]. Consistent results were observed across all subscales of the EORTC and FACT-C instruments. QoL was generally maintained during treatment for the global EORTC and FACT-C scales.. In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Cetuximab; Colorectal Neoplasms; Humans; Mutation; Patient Reported Outcome Measures; Proto-Oncogene Proteins B-raf; Quality of Life; Sulfonamides

Encorafenib plus cetuximab with or without binimetinib showed increased objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) compared with chemotherapy plus anti-EGFR in previously treated patients with BRAF V600E-mutated (mut) metastatic colorectal cancer (mCRC). Although no formal comparison was planned, addition of binimetinib to encorafenib plus cetuximab did not provide significant efficacy advantage.. This real-life study was aimed at evaluating safety, activity, and efficacy of encorafenib plus cetuximab with or without binimetinib in patients with BRAF V600E-mut mCRC treated at 21 Italian centers within a nominal use program launched in May 2019.. Out of 133 patients included, 97 (73%) received encorafenib plus cetuximab (targeted doublet) and 36 (27%) the same therapy plus binimetinib (targeted triplet). Most patients had Eastern Cooperative Group Performance Status (ECOG-PS) of 0 or 1 (86%), right-sided primary tumor (69%), and synchronous disease (66%). Twenty (15%) tumors were DNA mismatch repair deficiency (dMMR)/microsatellite instability (MSI)-high. As many as 44 (34%) patients had received two or more prior lines of therapy, 122 (92%) were previously exposed to oxaliplatin, and 109 (82%) to anti-vascular endothelial growth factor (anti-VEGF). Most frequent adverse events were asthenia (62%) and anti-EGFR-related skin rash (52%). Any grade nausea (P = 0.03), vomiting (P = 0.04), and diarrhea (P = 0.07) were more frequent with the triplet therapy, while melanocytic nevi were less common (P = 0.06). Overall, ORR and disease control rate (DCR) were 23% and 69%, respectively, with numerically higher rates in the triplet group (ORR 31% versus 17%, P = 0.12; DCR 78% versus 65%, P = 0.23). Median PFS and OS were 4.5 and 7.2 months, respectively. Worse ECOG-PS, peritoneal metastases, and more than one prior treatment were independent poor prognostic factors for PFS and OS. Clonality of BRAF mutation measured as adjusted mutant allele fraction in tumor tissue was not associated with clinical outcome.. Our real-life data are consistent with those from the BEACON trial in terms of safety, activity, and efficacy. Patients in good general condition and not heavily pretreated are those more likely to derive benefit from the targeted treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Humans; Proto-Oncogene Proteins B-raf; Sulfonamides

Patients with metastatic colorectal cancer with the. In this open-label, phase 3 trial, we enrolled 665 patients with. The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.. A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Cetuximab; Colorectal Neoplasms; Disease Progression; Electrocorticography; Female; Humans; Intention to Treat Analysis; Irinotecan; Kaplan-Meier Estimate; Male; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Sulfonamides; Survival Analysis

To determine the safety and preliminary efficacy of selective combination targeted therapy for. Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with. Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with. In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Folic Acid; Humans; Irinotecan; Male; Middle Aged; Mutation; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Sulfonamides; Survival Rate

Triplet and doublet regimens of encorafenib plus cetuximab with and without binimetinib, respectively, were approved in Japan for unresectable, metastatic, BRAF V600E-mutated colorectal cancer (mCRC) that had progressed after 1-2 prior chemotherapies. This early post-marketing phase vigilance (EPPV) study collected adverse drug reactions (ADRs) from Japanese patients to ensure safety measures as appropriate.. Patients with BRAF V600E mCRC who received the triplet or doublet regimens in Japan were selected for this study. ADRs were collected as spontaneous reports between November 27, 2020 and May 26, 2021. Serious ADRs were evaluated according to guidelines of the International Council for Harmonisation and the EudraVigilance list of Important Medical Event Terms.. An estimated 550 Japanese patients with mCRC received the triplet or doublet regimens during the 6-month EPPV period. Overall, 101 and 42 patients reported ADRs and serious ADRs, respectively. No ADRs leading to death were reported. The most frequently reported ADRs were nausea (17 patients), serous retinal detachment (16), decreased appetite (12), diarrhea (11), and vomiting (11). Among the important identified/potential risks that are defined in the risk management plans for encorafenib and binimetinib, eye disorder-related ADRs were observed in 32 patients, rhabdomyolysis-related ADRs in 12, hemorrhage-related ADRs in 7, and hepatic dysfunction-related ADRs in 7. Of 22 patients with serious eye disorders, 20 recovered or were recovering during the EPPV period.. The safety profile in this EPPV study was similar to that from the phase III BEACON CRC study and no new safety concerns were identified.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Humans; Mutation; Proto-Oncogene Proteins B-raf

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Cetuximab; Colorectal Neoplasms; Humans; Mutation; Proto-Oncogene Proteins B-raf; Sulfonamides

A 76-year-old woman was diagnosed with left-sided transverse colon cancer invading the pancreatic tail with multiple liver metastases and peritoneal dissemination. Preoperative diagnosis was cT4b(SI)N2aM1c(H3, P1), cStage Ⅳc, harboring BRAF V600E mutation. Transverse colostomy was performed, and FOLFOXIRI plus bevacizumab(BEV)was administered. After 12 chemotherapy cycles, the primary tumor and metastatic lesions showed partial response. Because of CEA elevating after 5-FU plus LV plus BEV as maintenance therapy was changed, the regimen was switched to encorafenib plus binimetinib plus cetuximab as the second-line chemotherapy. The patient developed dermatitis around the colostomy after the start of the second-line chemotherapy, resulting in temporally cetuximab monotherapy. After improvement of dermatitis, the patient resumed encorafenib plus binimetinib, improving liver metastases. Eight months after the start of the second- line, the patient has been administered with triple therapy and had stable disease status.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colorectal Neoplasms; Dermatitis; Female; Fluorouracil; Humans; Liver Neoplasms; Mutation; Proto-Oncogene Proteins B-raf

The patient was a 72-year-old man with a chief complaint of abdominal pain. We performed laparoscopic left hemicolectomy of the colon after descending colon cancer ileus stenting, and postoperative pathology was pT4aN0M0, pStage Ⅱb. In 1.5 years postoperatively, 2 liver metastases and 1 lymph node metastasis were found, and each was resected. Chemotherapy was initiated for multiple lung metastases. Genetic testing was positive for BRAF V600E mutation, and the patient received 8 mFOLFOXIRI plus bevacizumab therapy courses. After 15 5-FU plus LV plus bevacizumab courses, the patient had a brain infarction and lung metastasis reincreased. Chemotherapy was changed to encorafenib plus binimetinib plus cetuximab. On day 2, visual impairment was observed, and serous retinal detachment CTCAE Grade 2 was diagnosed. On day 7, the symptoms improved and one-step dose reduction was resumed. On day 2 of re-treatment, serous retinal detachment recurred and treatment was discontinued. On day 4 of re-treatment, the symptoms improved, another dose reduction was performed, and treatment was resumed. Since subjective MEK inhibitor-induced ocular symptoms are often minor, conducting an interview and early ophthalmologic diagnosis is recommended.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Male; Mitogen-Activated Protein Kinase Kinases; Mutation; Neoplasm Recurrence, Local; Proto-Oncogene Proteins B-raf; Retinal Detachment

This was a cohort study on genetic alterations in patients with BRAF. In total, 37 patients were included in this cohort. Genetic alterations in EGFR and in PIK3CA are associated with non-response. A greater fraction of non-responders (75%) versus responders (46%) had at least one genetic alteration in other genes than TP53, APC or BRAF. Secondary resistance mutations (n = 16 patients) were observed most frequently in the PI3K pathway (n = 6) and in receptor tyrosine kinases (n = 4), leading to increased upstream signalling.. Genetic alterations in the PI3K and upstream receptor tyrosine kinases were mostly associated with intrinsic and acquired resistance. By understanding these alterations, simultaneous or alternating treatments with targeted inhibitors might improve response duration.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biomarkers, Tumor; Carbamates; Cetuximab; Cohort Studies; Colorectal Neoplasms; DNA Mutational Analysis; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Retrospective Studies; Sulfonamides; Thiazoles

Recently the phase 3 BEACON trial showed that the combination of encorafenib, cetuximab, and binimetinib versus cetuximab and irinotecan/FOLFIRI improved overall survival in pre-treated patients with metastatic colorectal cancer (mCRC) with BRAF V600E mutation. However, whether the benefits of these therapies justify their high costs has not been estimated in the USA. The purpose of this study was to evaluate the cost-effectiveness of BEC (binimetinib, encorafenib, and cetuximab), EC (encorafenib and cetuximab), and CI/CF (cetuximab with irinotecan or FOLFIRI) in patients with BRAF V600E-mutated mCRC after first- and second-line therapy.. A Markov model was constructed to determine the costs and effects of BEC, EC, and CI/CF on the basis of BEACON trial outcomes data. Health outcomes were measured in life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Deterministic and probabilistic sensitivity analyses characterized parameters influencing cost-effectiveness. Subgroup analyses were conducted as well.. The QALYs gained in BEC, EC, and CI/CF were 0.62, 0.54, and 0.40, respectively. BEC resulted in ICERs of $883,895.73/QALY and $1,646,846.14/QALY versus CI/CF and EC, respectively. Compared with CI/CF, the ICER was $435,449.88/QALY in EC. The most sensitive parameters in the comparison among the three arms were the utilities of progressive disease and progression-free survival. Probabilistic sensitivity analyses showed that the probability of BEC and EC being cost-effective was 0%. In subgroup analyses, the ICER remained above the willingness-to-pay threshold of $150,000 per QALY.. BEC and EC were not cost-effective regimens for patients with pre-treated mCRC with BRAF V600E mutation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Cetuximab; Colorectal Neoplasms; Cost-Benefit Analysis; Fluorouracil; Humans; Proto-Oncogene Proteins B-raf; Quality-Adjusted Life Years; Sulfonamides; United States

Topics: Acute Kidney Injury; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Cetuximab; Colorectal Neoplasms; Glomerular Filtration Rate; Humans; Kidney; Male; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Recovery of Function; Risk Factors; Sulfonamides; Treatment Outcome

Topics: Benzimidazoles; Carbamates; Cetuximab; Colorectal Neoplasms; Humans; Proto-Oncogene Proteins B-raf; Sulfonamides

Topics: Benzimidazoles; Carbamates; Cetuximab; Colorectal Neoplasms; Humans; Proto-Oncogene Proteins B-raf; Sulfonamides

Topics: Benzimidazoles; Carbamates; Cetuximab; Colorectal Neoplasms; Humans; Proto-Oncogene Proteins B-raf; Sulfonamides

Topics: Benzimidazoles; Carbamates; Cetuximab; Colorectal Neoplasms; Humans; Proto-Oncogene Proteins B-raf; Sulfonamides

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Cetuximab; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Drug Approval; Humans; Mutation; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Sulfonamides

RAS signaling is a promising target for colorectal cancer (CRC) therapy, and a variety of selective inhibitors have been developed. However, their use has often failed to demonstrate a significant benefit in CRC patients. Here, we used patient-derived organoids (PDOs) derived from a familial adenomatous polyposis (FAP) patient to analyze the response to chemotherapeutic agents targeting EGFR, BRAF and MEK. We found that PDOs carrying KRAS mutations were resistant to MEK inhibition, while those harboring the BRAF class 3 mutation were hypersensitive. We used a systematic approach to examine the phosphorylation of RAS effectors using reverse-phase protein array (RPPA) and found increased phosphorylation of MEK induced by binimetinib. A high basal level of ERK phosphorylation and its rebound activation after MEK inhibition were detected in KRAS-mutant PDOs. Notably, the phosphorylation of EGFR and AKT was more closely correlated with that of MEK than that of ERK. Transcriptome analysis identified MYC-mediated transcription and IFN signaling as significantly correlated gene sets in MEK inhibition. Our experiments demonstrated that RPPA analysis of PDOs, in combination with the genome and transcriptome, is a useful preclinical research platform to understand RAS signaling and provides clues for the development of chemotherapeutic strategies.

Topics: Adenomatous Polyposis Coli; Adult; Animals; Benzimidazoles; Cell Line, Tumor; Colorectal Neoplasms; Exome; Humans; Interferons; Male; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mice; Mice, Inbred NOD; Mutation; Organoids; Phosphorylation; Proto-Oncogene Proteins c-myc; ras Proteins; Sequence Analysis, RNA; Transcriptome

Topics: Benzimidazoles; Carbamates; Cetuximab; Colorectal Neoplasms; Humans; Proto-Oncogene Proteins B-raf; Sulfonamides

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carbamates; Cetuximab; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Humans; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome

The irinotecan-induced phosphokinome changes in colorectal cancer (CRC) cells were used to guide the selection of targeted agents to be tested in combination with irinotecan.. Phosphokinome profiling with peptide arrays of tumour samples from nude mice xenografted with HT29 cells and treated or not with an effective dose of irinotecan was used to identify signalling pathways activated by irinotecan treatment. Then, drugs targeting these pathways were combined in vitro with irinotecan to test potential synergistic effect. The interactions between these drug combinations were assessed by a dose matrix approach. Confirmation of the most potential combination has been confirmed in vivo in xenografted mice.. Irinotecan induced in vivo the activation of AKT and MEK1 phosphorylation. The dose matrix approach showed that BKM120 (PI3K inhibitor) and MEK162 (MEK inhibitor) are synergistic in vitro and in vivo with a cytostatic and cytotoxic effect, while combination of BKM120 and irinotecan or MEK162 and irinotecan are only additive or even antagonistic. However, the triple combination of SN38, BKM120 and MEK162 showed a better synergistic effect that BKM120 and MEK162, indicating that the cells need to inhibit both AKT and ERK pathways to become more sensitive to irinotecan-based chemotherapies.. Analysis of chemotherapy-induced phosphokinome changes helps to elucidate the mechanisms of drug resistance and to guide the selection of targets for combination therapies with synergistic activity.

Topics: Aminopyridines; Animals; Benzimidazoles; Camptothecin; Cell Proliferation; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; HT29 Cells; Humans; Irinotecan; MAP Kinase Kinase 1; Mice; Molecular Targeted Therapy; Morpholines; Protein Kinase Inhibitors; Signal Transduction; Xenograft Model Antitumor Assays

Preclinical evidence demonstrates that mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway inhibition increases sensitivity to 5-fluorouracil (5-FU) in colorectal cancer (CRC) cell lines and xenografts. Here, we aimed to investigate how CRC cell sensitivity to this combination is correlated to Kirsten rat sarcoma (KRAS) and proto-oncogene B-rapidly accelerated fibrosarcoma (BRAF) mutation, that are common in CRC and often lead to resistance to chemotherapy.. Wild-type and mutant KRAS/BRAF human CRC cell lines were treated with escalating doses of 5-FU or trifluridine with MEK162 (MEK1/2 inhibitor) for 72 h. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and synergism expressed by the combination index was calculated using CalcuSyn.. Evidence of synergistic antitumor activity was observed for the majority of human CRC cell lines treated with MEK162 plus 5-FU (4/6) or trifluridine (7/9). Synergism was greater in KRAS- or BRAF-mutant cell lines compared to wild-type KRAS/BRAF CRC cell lines.. The combination of MEK inhibition and trifluridine is worthwhile advancing in clinical development, particularly for treatment-refractory KRAS- or BRAF-mutated metastatic CRC.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms; Fluorouracil; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins p21(ras); Trifluridine

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

The objective of tailoring medicines for cancer patients according to the molecular profile of their disease holds great promise for the improvement of cancer therapy. Nevertheless, this approach has been limited, in part, due to the lack of predictive and informative preclinical studies. Herein, we describe an assessment of the therapeutic potential of targeting PI3K/mTOR and MAPK signaling in genetically defined mouse models of colorectal cancer mirroring disease subtypes targeted for novel therapy in the FOCUS4 trial. Our studies demonstrate that dual PI3K/mTOR inhibition is highly effective in invasive adenocarcinoma models characterized by combinatorial mutations in Apc and Pten; Apc and Kras; and Apc, Pten and Kras. MEK inhibition was effective in the combinatorial Apc and Kras setting, but had no impact in either Apc Pten mutants or in Apc Pten Kras triple mutants. Furthermore, we describe the importance of scheduling for combination studies and show that although no additional benefit is gained in Apc Pten mice, combination of PI3K/mTOR and MAPK inhibition leads to an additive benefit in survival in Apc Kras mice and a synergistic increase in survival in Apc Pten Kras mice. This is the first study using robust colorectal cancer genetically engineered mouse models to support the validity of PI3K/mTOR and MEK inhibitors as tailored therapies for colorectal cancer and highlight the potential importance of drug scheduling in the clinic.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Benzimidazoles; Colorectal Neoplasms; Disease Models, Animal; Drug Screening Assays, Antitumor; Genes, APC; Imidazoles; MAP Kinase Kinase Kinases; Mice, Transgenic; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); PTEN Phosphohydrolase; Quinolines; Tumor Burden