piperidines and Adenocarcinoma-of-Lung

The echinoderm microtubule-associated protein-like 4 gene (EML4) and anaplastic lymphoma kinase gene (ALK) fusion is the most common ALK rearrangements in non-small cell lung cancer (NSCLC). Herein, we firstly report that coexistence of a novel Neurobeachin (NBEA)-ALK, EML4-ALK double-fusion is sensitive to alectinib.. Hematoxylin-eosin staining (HE), fluorescent in situ hybridization (FISH), and next-generation sequencing (NGS) was performed on the biopsy sample.. The patient responded to alectinib as a second-line treatment and achieved stable disease for 11 months, without significant symptoms of toxicity. Significantly, the liquid biopsy also validated clinical benefit, with the disappearance of NBEA-ALK and EML4-ALK fusion variants. We also provided a comprehensive review of all 50 ALK fusion genes in NSCLC.. This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. Alectinib may be a viable therapeutic option for NSCLC patients with double-ALK fusion, and liquid biopsy could dynamically monitor clinical curative effect.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Carrier Proteins; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Nerve Tissue Proteins; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Oncogene Proteins, Fusion; Piperidines; Prognosis

ALK translocation is the 3rd most frequent genetic aberration in lung adenocarcinoma, and several inhibitors are now clinically available in first and second line settings. Accordingly, molecular diagnostics of ALK-positive lung cancer is very important and can be done with the rational combination of several methods. All international recommendations suggest that, except for cytological samples, screening technology for ALK-positive tumors is immunohistochemistry using a validated test. It is highly recommended that in case of ALK protein positive samples gene translocation must be confirmed by fluorescent in situ hybridization (FISH). In case of cytological samples FISH technique must be used as ALK diagnostics. In equivocal cases the genetic alteration of ALK can be confirmed by alternative molecular techniques such as next generation sequencing or RNAbased PCR methods. Upon administration of ALK inhibitors, acquired resistance is frequent which is mostly due to ALK amplification and/or mutation. It is evident that the diagnostics of these secondary ALK gene alterations must be done from recurrent tumors or circulating nucleic acids.. Az ALK gén transzlokációja a harmadik leggyakoribb, terápiás szempontból hasznosítható genetikai eltérés a tüdõ adenokarcinómáiban, és manapság már elsõ- és másodvonalú terápiákban több inhibitor áll rendelkezésre. Ezen okoknál fogva nagy jelentõsége van az ALK-pozitív tüdõrák molekuláris diagnosztikájának, amit több módszer racionális kombinációjával lehet végezni. A nemzetközi ajánlások megegyeznek abban, hogy a citológiai minták kivételével más típusú formalinfixált, paraffinos anyagok esetében az ALK-pozitív esetek szûrése a protein kimutatásának validált immunhisztokémiai módszerével történik. Az ALK proteinre pozitív esetekben a géntranszlokáció jelenlétét fluoreszcens in situ hibridizációval (FISH) célszerû megerõsíteni. Citológiai minták esetében az ALK gén transzlokációját elsõdlegesen FISH-módszerrel kell végezni. A kérdéses eredményû esetekben a genetikai eltérés tisztázására újgenerációs szekvenálást vagy RNS-alapú PCR-technikákat lehet alkalmazni. Az ALK-inhibitorok klinikai alkalmazása során gyakran alakul ki rezisztencia, aminek leggyakoribb oka az ALK gén amplifikációja és/vagy mutációi. Ezek molekuláris diagnosztikájának alapja a recidív daganatszövet vagy a vérben keringõ nukleinsav kell, hogy legyen.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Biopsy, Needle; Carbazoles; Crizotinib; Early Detection of Cancer; Gene Expression Regulation, Neoplastic; Humans; Hungary; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Molecular Targeted Therapy; Piperidines; Polymerase Chain Reaction; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Risk Assessment; Sulfones; Survival Analysis; Translocation, Genetic; Treatment Outcome

Vandetanib is a once-daily oral multi-target inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection (RET) tyrosine kinases. The current study aimed to evaluate the effect and safety of vandetanib administered in refractory advanced lung adenocarcinoma patients.. Five patients who accepted chemotherapy and Tarceva therapy as first- and second-line treatments received vandetanib (300 mg, oral, once daily).. The effects are stable disease on two patients (40%) and progressive disease on three patients (60%). With a median follow-up of 36 months, one patient remained on follow-up. The median progression free survival (PFS) is 2 months, and the mean overall survival is 22.6 months. The adverse events include rash (n=2), skin change (n=2), paronychia (n=2), asymptomatic QTc prolongation (n=2), ST-T change (n=1), diarrhea (n=1), and increased transaminase (n=1).. There were lower incidences of severe side effects with vandetanib therapy in refractory advanced lung adenocarcinoma patients. The results of effect and safety of vandetanib are similar with the related reviewed articles.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Male; Middle Aged; Piperidines; Quinazolines

If anaplastic lymphoma kinase (ALK) gene rearrangement in lung cancer is identified, ALK-tyrosine kinase inhibitors (ALK-TKIs) can be an effective treatment. However, the details of drug-induced lung injury (DILI) caused by ALK-TKI, which can be a serious side effect of ALK-TKIs, remains unclear. This study aimed to investigate the clinical features and the onset risk factors of DILI by ALK-TKIs in clinical practice.. The clinical features of 56 consecutive patients who received crizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were retrospectively examined. Among these, patients diagnosed with DILI due to ALK-TKIs were evaluated in terms of clinical features and parameters. Each clinical parameter before the administration of ALK-TKIs was compared between the DILI onset group and the non-onset group.. A total of seven cases were diagnosed with DILI due to ALK-TKIs; no DILI-related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute.. Extra caution for DILI due to ALK-TKIs may be needed when recommending ALK-TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK-TKIs show an OP pattern.. Significant findings of the study: Extra caution is needed when recommending ALK-TKIs for patients over 64 years of age or those with decreased renal function. Computed tomography images of the majority of patients with DILI by ALK-TKIs show an OP pattern.. The same or a different ALK-TKI may be considered as a treatment option after the onset of DILI, based on careful judgment.

Topics: Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Carcinoma, Squamous Cell; Crizotinib; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Lung Injury; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Risk Factors; Sulfones; Survival Rate

Anaplastic lymphoma kinase (ALK) rearrangement, which is mostly showed as fused with echinoderm microtubule-associated protein-like 4 gene (EML4), accounts 3-7% of all common mutations in non-small lung cancer (NSCLC). An intergenic region (chr2: 30,193,816), which located on upstream of the adjacent ALK gene, was never been reported as a ALK patterner before.. A 56-year-old female patient who had symptoms of persistent cough and shortness of breath visited our facility on April 24, 2022. The chest computerized tomography (CT) examination revealed a massive right hydrothorax. After draining pleural effusion, a hilar mass accompanied multiple nodules in both lungs could been seen in image. Tracheoscopy revealed neoplasm in the medial segment of the middle lobe of the right lung, and the patient was diagnosed as lung adenocarcinoma pathologically. It tested positive for cytokeratin (CK) 7, NapsinA, ALK, and thyroid transcription factor-1 (TTF-1). Next generation sequence testing confirmed the presence of the intergenic region (chr2: 30,193,816)-ALK fusion in the tumor tissue. The patient was subsequently treated with Alectinib, and her symptoms are obviously relieved, the right hilar mass and metastatic nodule were reduced in the reexamination after three months.. The intergenic region (chr2: 30,193,816)-ALK fusion, which is firstly reported in lung adenocarcinoma, is a mutation with expression significance. It shows sensitivity to Alectinib.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Female; Humans; Lung Neoplasms; Middle Aged; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

The incidence of lung cancer in pregnancy is increasing because of an increase in cigarette smoking among young women, air pollution, and advanced maternal age. This is the third case report of a woman with metastatic anaplastic lymphoma kinase (ALK)-positive lung adenocarcinoma treated with alectinib during pregnancy. The patient was diagnosed with lung cancer at 26 weeks' gestation. Her condition rapidly progressed to disseminated intravascular coagulation accompanied by hypoxemia. After 5 days of treatment with alectinib 600 mg twice daily and best supportive care, the patient's symptoms quickly resolved. She delivered a healthy male newborn at 39 weeks' gestation. At birth, the alectinib concentration was 4.3 times higher in maternal plasma than that in newborn plasma (299.0 vs 69.2 ng/mL). The concentrations of alectinib in the amniotic fluid and the placenta were 27.3 ng/mL and 1136.25 ng/g, respectively. The alectinib concentration in the maternal milk (152 ng/mL) indicated that this drug could be excreted through the breast milk. At 12 months after the diagnosis, the mother had recovered well, and no developmental anomalies were observed in the infant.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Infant, Newborn; Lung Neoplasms; Male; Piperidines; Pregnancy; Protein Kinase Inhibitors

Topics: Adenocarcinoma of Lung; alpha-Thalassemia; Carbazoles; Erythrocytes, Abnormal; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines

The echinoderm microtubule associated protein-like 4 gene (EML4) encodes the predominant anaplastic lymphoma kinase (ALK) fusion partner in non-small-cell lung cancer (NSCLC); however, the dynactin subunit 1 (DCTN1)-ALK rearrangement is extremely rare. The co-occurrence of primary epidermal growth factor receptor (EGFR) T790M mutation with EGFR exon 19 deletion (del) in patients with NSCLC is uncommon. Here we report a female lung adenocarcinoma patient with brain metastases and possible coexistence of primary EGFR T790M mutation/EGFR exon 19 del/DCTN1-ALK translocation. The patient received multiline treatment including chemotherapy, antivascular, and targeted therapies. To overcome developed resistance to chemotherapy or targeted therapy to prolong overall survival, the patient's circulating tumor DNA (ctDNA) was dynamically monitored. The patient responded to successive osimertinib and alectinib treatment, and alectinib achieved a nearly complete response for lung and brain lesions after she acquired osimertinib resistance. Furthermore, we summarize 22 published cases of patients with lung adenocarcinoma with concurrent EGFR mutation and ALK rearrangement, including details of clinical characteristics, natural history, and pertinent therapy of this uncommon tumor subtype. This literature review shows that EGFR inhibition was an indispensable aspect of the treatment of patients with EGFR/ALK co-alterations in the pre-alectinib era and that ALK inhibition with crizotinib did not show more eye-catching therapeutic results. Considering the effectiveness achieved by alectinib, this case study provides a new perspective for the treatment of lung cancer brain metastasis patients with concurrent EGFR/ALK mutations.

Topics: Acrylamides; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Aniline Compounds; Brain; Carbazoles; Carcinoma, Non-Small-Cell Lung; Dynactin Complex; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors

Topics: Adenocarcinoma of Lung; Carbazoles; Humans; Lung Neoplasms; Neoplasm Metastasis; Organophosphorus Compounds; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases

We report a rare case of stage IV pulmonary combined large-cell neuroendocrine carcinoma (LCNEC) and adenocarcinoma (ACA), both demonstrating anaplastic lymphoma kinase (

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Neuroendocrine; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Genomic fusions of anaplastic lymphoma kinase (ALK) are a well-established therapeutic target in non-small-cell lung cancer (NSCLC). Although various ALK fusion variants have been identified in NSCLC, their responses to ALK tyrosine-kinase inhibitors (TKIs) are heterogeneous. We report the case of a 71-year-old female patient diagnosed with lung adenocarcinoma with liver metastases. A novel CTNND1 (exon 14)-ALK (exon 20) fusion was identified from the biopsy sample by next-generation sequencing (NGS) and validated by immunohistochemistry (IHC) staining. Alectinib was administered, and the patient soon achieved partial response (PR). The progression-free survival (PFS) exceeded 15 months as of January 25, 2022. Our findings expand the spectrum of ALK rearrangements and provide a potential treatment option for lung adenocarcinoma patients with CTNND1-ALK fusions.

Topics: Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

ALK (anaplastic lymphoma kinase) gene rearrangements have been reported in 3-5% of NSCLC patients. Different ALK fusion forms can mediate different downstream signaling pathways and may exhibit different sensitivities to ALK tyrosine kinase inhibitors (TKIs). To identify more fusion partners that are sensitive to ALK-TKIs, we present a case of 46-year-old woman with stage IV lung adenocarcinoma. NGS panel analysis suggested that a novel SSFA2-ALK fusion was identified in this patient. Moreover, this fusion was validated through IHC (VENTANA ALK (D5F3) antibody) and FISH (ZytoLight ALK Break Apart FISH Probe). Importantly, to the best of our knowledge, there is no report about SSFA2-ALK fusion in solid cancers. Moreover, the patient achieved an admirable response to alectinib, with a clinical evaluation of complete response (CR). In summary, our findings expand the spectrum of ALK fusion patterns and provide robust evidence for the precise administration of alectinib in the future.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Humans; In Situ Hybridization, Fluorescence; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

The Keap1-Nrf2 system is the master regulator of the cellular response against oxidative and xenobiotic stresses. Constitutive activation of Nrf2 is frequently observed in various types of cancers. Nrf2 hyperactivation induces metabolic reprogramming in cancer cells, which supports the increased energy demand required for rapid proliferation and confers high-level resistance against anticancer radio/chemotherapy. Hence, Nrf2 inhibition has emerged as an attractive therapeutic strategy to counter such acquired resistance in Nrf2-activated tumors. We previously identified Halofuginone (HF) as a promising Nrf2 inhibitor. In this study, we pursued preclinical characterization of HF and found that while HF markedly reduced the viability of cancer cells, it also caused severe hematopoietic and immune cell suppression in a dose-dependent manner. Hence, to overcome this toxicity, we decided to employ a nanomedicine approach to HF. We found that encapsulation of HF into a polymeric micelle (HF micelle; HFm) largely relieved the systemic toxicity exhibited by free HF while maintaining the tumor-suppressive properties of HF. LC-MS/MS analysis revealed that the reduction in the magnitude of adverse effects was the result of the ability to release HF from the HFm core in a slow and sustained manner. These results thus support the contention that HFm will potentially counteract Nrf2-activated cancers in the clinical settings.

Topics: Adenocarcinoma of Lung; Chromatography, Liquid; Humans; Kelch-Like ECH-Associated Protein 1; Lung Neoplasms; Micelles; Nanoparticles; NF-E2-Related Factor 2; Oxidative Stress; Piperidines; Quinazolinones; Tandem Mass Spectrometry

A 55-year-old Chinese man with a right lung mass and lymph node metastasis (T4N3M0 IIIB) was diagnosed with lung adenocarcinoma after a CT-guided biopsy. With the wide application of next-generation sequencing (NGS) in tumour detection, we found a rare CCDC85A-ALK fusion. The patient received alectinib, which had marked efficacy. This is the first report of a lung adenocarcinoma patient harbouring a new uncommon anaplastic lymphocyte kinase fusion that showed a remarkable response to alectinib. NGS aids in selecting treatment in non-small cell lung cancer patients.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors

A remarkable concurrence of an EGFR mutation and an EML4-ALK fusion (double positive) occasionally occurs within a narrow number of patients. Previous studies using targeted therapy on EGFR/ALK co-mutated patients have commonly focused on single tyrosine kinase inhibitors (TKIs) or on the sequential use of EGFR-TKIs and ALK-TKIs. At present, no consensus exists regarding the treatment of patients with double positive mutations. The effectiveness of precision therapy also remains unknown.. A 53-year-old female non-smoker who described recurrent coughing and blood in her sputum over a month-long interval was examined at a local hospital.. Using computed tomography (CT) and positron emission tomography CT (PET-CT), the patient was diagnosed with Stage IVb lung adenocarcinoma (T4N3M1).. The patient had a novel ALK-RAB10 rearrangement identified using DNA sequencing, which, at the transcript level, was actually a canonical ALK fusion that caused a response to alectinib therapy.. The patient has achieved partial remission (PR), with a progression free survival (PFS) of 16 months, and continues to benefit.. Our results may indicate differential sensitivities to TKIs in patients harboring an EGFR mutation and an ALK rearrangement. Our patient's response to alectinib, instead of to EGFR-TKIs, may lead to an expanded list of alectinib beneficiaries who have rare gene co-alterations in lung adenocarcinoma.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Piperidines; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors

The echinoderm microtubule-associated protein-like 4 gene and anaplastic lymphoma kinase gene (EML4-ALK) is the most frequent fusion variant of ALK rearrangements in non-small cell lung cancer (NSCLC). With the widespread application of next-generation sequencing (NGS), more fusions and co-mutations of EML4-ALK have been discovered. Complex co-mutation of EML4-ALK fusions together with BRAF V600E, though rarely occurred, also deserves attention to determine the standard of caring these patients. Herein, we report a case of lung adenocarcinoma harboring a complex ALK fusion that coexisted with a BRAF mutation, as tested by DNA-NGS prior to treatment.. A 51-year-old non-smoking man, without any symptoms, was admitted to hospital due to small pulmonary nodules and enlarged supraclavicu larlymph nodes found in health checkup.. He was diagnosed with stage IVB (T4N3M1c) lung adenocarcinoma. BRAF V600E (abundance 3.75%) mutation and a novel thus little-understood EML4-ALK (E13, A5; abundance 2.16%) fusion were identified by DNA-NGS analysis of lymph node biopsy tissue in December 2019.. Darafenib plus trametinib targeted therapy and chemotherapy were given firstly, but tumor progression was not inhibited. The ALK inhibitor alectinib was prescribed then.. The patient exhibited a rapid disease response to ALK tyrosine kinase inhibitors alectinib with a complete remission of widespread metastatic disease and progression-free survival of more than 26 months, but not to darafenib plus trametinib targeted BRAF V600E therapy. Re-analyzed the patient's DNA-NGS original data, showed it is a rare and complex EML4-ALK (E13, A5, A20) fusion in fact. Additional RNA-NGS analysis showed it verified to be a canonical EML4-ALK (E13, A20) fusion transcript and coexisting with a BRAF V600E mutation.. This case suggests that for patients with rare or complex EML4-ALK fusions at DNA level, additional RNA-NGS is necessary to verify its functionality as early as possible. Targeting EML4-ALK firstly may be more preferable despite the coexisting of BRAF V600E.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Microtubule-Associated Proteins; Middle Aged; Mutation; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; RNA

Lung cancer complicated with Trousseau syndrome (TS) or disseminated intravascular coagulation (DIC) has a severe prognosis. We herein report an elderly lung cancer patient who presented with a critically ill condition due to concomitant TS and DIC and responded dramatically to alectinib. There are no rules regarding treatment indications based on the age or severity of critically ill patients. If the patient's cancer cells are positive for anaplastic lymphoma kinase rearrangement, alectinib is worthwhile to administer, even in a critically ill condition. In our patient, anticoagulation failed to suppress the TS complications. We also report how to prevent the recurrence of TS.

Topics: Adenocarcinoma of Lung; Aged; Carbazoles; Critical Illness; Disseminated Intravascular Coagulation; Humans; Lung Neoplasms; Piperidines

In May 2020 and February 2021, capmatinib and tepotinib, respectively were approved by the Food and Drug Administration (FDA) for the treatment of metastatic non-small cell lung carcinoma harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations. Herein, we present a case of intolerable peripheral edema caused by tepotinib, in which MET inhibitor could be continued by switching to capmatinib. Peripheral edema has been identified as one of the most common adverse events in capmatinib and tepotinib; however, there is no unified management for this adverse event. This is the first report that two MET inhibitors have different effects on the development of peripheral edema, and that the MET inhibitors can be continued by switching these drugs.

Topics: Adenocarcinoma of Lung; Aged; Antineoplastic Agents; Benzamides; Brain Neoplasms; Edema; Extremities; Humans; Imidazoles; Lung Neoplasms; Male; Piperidines; Pyridazines; Pyrimidines; Triazines

More than 20 types of ALK fusion variant subtypes have been identified, including different fusion partner genes or EML4-ALK fusions with different breakpoints. However, different ALK fusions show different sensitivities to ALK-tyrosine kinase inhibitors (ALK-TKIs) and the emergence of rare fusions brings great challenges to the target therapy in clinic. We report a rare EML4-ALK (E6;A18) fusion in a patient with lung adenocarcinoma that responded well to alectinib. This is the second case of this rare variant reported but the first report of response to an ALK-TKI. This evidence is the first to show that alectinib may be effective for this rare fusion type of non-small cell lung cancer, and these findings have important implications for drug selection in patients with this subtype. Further studies are needed to understand the function of this variant.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Exons; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

Anaplastic lymphoma kinase (ALK) rearrangement is the second most common targetable oncogene-dirven gene in nonsmall cell lung cancer. Owing to the advanced sequencing technologies, new partner genes of ALK have been constantly detected.. A 42-year-old Chinese woman went to our hospital with the chief complaint of cough and expectoration for 1 month. The patient had no fever, chest pain, and hemoptysis.. She was diagnosed with advanced lung adenocarcinoma. The patient underwent lung biopsy guided by computed tomography and pathology showed poorly differentiated adenocarcinoma. To explore possibility of targeted therapy, the tumor samples were subjected to next-generation sequencing, and a rare 3 ALK fusion variant ALK-LRRN2, LTBP1-ALK, and HIP1-ALK was identified.. The patient subsequently received alectinib treatment, and achieved partial response. No significant drug related adverse reactions were found during alectinib treatment. The progression-free survival achieved 25 months.. Together, we identified a rare triple ALK fusion variant, ALK-LRRN2, LTBP1-ALK and HIP1-ALK, in a patient with lung adenocarcinoma. The patient benefited from alectinib treatment, which could provide a certain reference for the patients with such gene alteration.

Topics: Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Adhesion Molecules, Neuronal; DNA-Binding Proteins; Drug Resistance, Neoplasm; Female; Gene Fusion; Humans; Latent TGF-beta Binding Proteins; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Gene Rearrangement; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Patient Acuity; Piperidines

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Biomarkers, Tumor; Carbazoles; Cytoskeletal Proteins; Female; Humans; Lung Neoplasms; Middle Aged; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Piperidines; Prognosis; Sequence Analysis, RNA

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

Drug-induced immune hemolytic anemia (DIIHA) is a rare condition with an increasing incidence associated with the frequent use of certain drugs. An 85-year-old woman with lung adenocarcinoma prescribed alectinib complained of dyspnea on exertion at our hospital. Based on her laboratory tests results on admission, we focused on the clinical course of anemia and hemolysis progression after alectinib administration. The patient's anemia and hemolysis gradually improved after discontinuation of alectinib, leading to a diagnosis of alectinib-induced IHA, presented here as the first case encountered in a patient with lung adenocarcinoma. Furthermore, we discuss the importance of correlating clinical laboratory findings in DIIHA.

Topics: Adenocarcinoma of Lung; Aged, 80 and over; Anemia, Hemolytic; Carbazoles; Female; Humans; Lung Neoplasms; Piperidines

Even though alectinib is a potent second-generation ALK inhibitor with a favorable safety profile, alectinib-induced interstitial lung disease (ILD) could be fatal. There are case reports described successful alectinib rechallenge in mild ILD. However, the feasibility and safety of rechallenge in severe cases remains to be elucidated.. A 76-year-old female was a case of stage IV lung adenocarcinoma harboring ALK rearrangement. Respiratory failure following severe ILD developed one month after alectinib administration. She received mechanical ventilation in intensive care uint. ILD subsided gradually after methylprednisolone pulse therapy and discontinuation of alectinib.. Given that the ALK inhibitors are the treatment of choice for advanced lung cancer patients with ALK rearrangement. Our report demonstrated the potential feasibility of alectinib re-use in cases of severe druginduced ILD.

Topics: Adenocarcinoma of Lung; Aged; Carbazoles; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Anaplastic lymphoma kinase (ALK) rearranged lung cancers represent 4% to 6% of all pulmonary adenocarcinomas, and echinoderm microtubule associated protein like 4 (EML4)-ALK fusions are the most common subgroup. Herein, we report a case of two successive drug reactions due to ALK inhibitors. A 69-year-old female with stage IVB EML4-ALK fused lung adenocarcinoma developed a generalized morbilliform eruption 10 days after starting alectinib. Skin biopsy findings were consistent with a drug reaction. Her findings resolved after alectinib was discontinued. Another ALK inhibitor, lorlatinib was started and she developed multiple asymptomatic cutaneous and oral nodules 4 months later. Biopsies from these nodules showed sarcoidal granulomas without evidence of metastases or infection. ALK inhibitors are associated with numerous adverse events, including various cutaneous eruptions. However, a sarcoidal drug reaction involving the skin has not been reported. Identification of drug reactions to targeted therapy can avoid long-term sequelae and misinterpretation of the clinical findings as disease progression or infection.

Topics: Adenocarcinoma of Lung; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Biopsy; Carbazoles; Cell Cycle Proteins; Drug-Related Side Effects and Adverse Reactions; Female; Granuloma; Humans; Lactams; Microtubule-Associated Proteins; Neoplasm Staging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Sarcoidosis; Serine Endopeptidases; Skin; Withholding Treatment

Mesenchymal-epithelial transition (MET) pathway activation is associated with the mechanisms that influence properties affecting cancer cell survival and invasiveness. The MET exon 14 skipping mutation (METex14del) is found in 2%-3% of patients with non-small cell lung cancer (NSCLC). Previous studies reported that NSCLC patients harboring a METex14del responded well to MET-tyrosine kinase inhibitors (TKIs), including tepotinib. Tepotinib is a highly selective, once-daily oral MET inhibitor that has shown promising clinical activity in patients with NSCLC with METex14del. The Food and Drug Administration accepted a new drug application for tepotinib as a treatment for patients with metastatic NSCLC harboring METex14del in February 2021 [Correction added on 5 March 2021, after first online publication: the FDA approval date for tepotinib has been corrected from 'September 2019' to 'February 2021'.]. However, in the previous clinical trials involving MET-TKIs, only patients with stable central nervous system metastases were eligible, and those with untreated symptomatic brain metastases (BMs) were excluded. Therefore, the efficacy and safety of MET-TKIs in that population remains unknown. We herein report a case of dramatic intracranial response to tepotinib in a patient with symptomatic BMs from lung adenocarcinoma harboring METex14del. In the current report, the symptoms derived from multiple BMs (headache and loss of appetite) rapidly disappeared, and brain magnetic resonance imaging (MRI) examination showed that all the lesions were too small to measure only 23 days after the commencement of tepotinib. For NSCLC patients with multiple BMs, whole-brain irradiation is a standard-of-care therapy, but its adverse effects on neurocognition are concerning. Tepotinib might therefore be a therapeutic option for NSCLC patients with symptomatic multiple BMs harboring METex14del.

Topics: Adenocarcinoma of Lung; Aged; Exons; Female; Humans; Lung Neoplasms; Mutation; Piperidines; Proto-Oncogene Proteins c-met; Pyridazines; Pyrimidines

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.

Topics: Adenocarcinoma of Lung; Aged; Aminopyridines; Carbazoles; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Muscle, Skeletal; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Pyrazoles

Topics: Adenine; Adenocarcinoma of Lung; Aged; ErbB Receptors; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lung Neoplasms; Male; Neoplasms, Second Primary; Piperidines; Protein Kinase Inhibitors

Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements are found in ~ 5% of patients with non-small cell lung cancer (NSCLC). Several tyrosine kinase inhibitors (TKIs) have been developed for treatment of so-called ALK-positive NSCLC. In cases of tumor progression during treatment with second-generation ALK-TKIs, such as alectinib, brigatinib, or ceritinib, National Comprehensive Cancer Network guidelines propose a switch to lorlatinib, a third-generation ALK-TKI, or to cytotoxic chemotherapy. However, they do not mention switching to other second-generation ALK-TKIs. Here, we present a rare case of a 53-year-old Japanese woman, who had never smoked, with ALK-positive lung adenocarcinoma who survived alectinib-resistant postoperative recurrence for 4 years by switching to ceritinib. She underwent curative resection for lung adenocarcinoma, but the cancer recurred at the bronchial stump and mediastinal lymph nodes. After platinum-doublet chemotherapy, the patient still had a single growing liver metastasis, but the tumor was found to harbor EML4-ALK rearrangement. Therefore, the patient started to take ALK-TKIs. Alectinib was the second ALK-TKI used to treat this patient. Alectinib shrank the liver metastasis, which was surgically resected. The tumor relapsed again during continued treatment with alectinib, which was switched to ceritinib. Ceritinib was effective for the relapsed tumor and treatment continued well for 4 years. This case report suggests that, in case of tumor progression during treatment with a second-generation ALK-TKI, switching to another second-generation ALK-TKI may be one of the treatment options. Further analyses are warranted to find robust markers to determine which ALK-TKI is best for each patient.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sulfones

We report an anaplastic lymphoma kinase (ALK)-positive patient shows a poor response to the ALK inhibitor alectinib due to the high expression of programmed death-ligand 1 (PD-L1). After treatment with alectinib, the pathological form changed from adenocarcinoma into squamous cell carcinoma without novel genetic changes. This case may reveal a direct relationship between ALK mutation and a high level of PD-L1 expression.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; B7-H1 Antigen; Carbazoles; Carcinoma, Squamous Cell; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors

Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown a high response rate and long progression-free survival in primary treatment of ALK-positive non-small-cell lung cancer (NSCLC). De novo resistance or refractory subtype is rare event. Herein, we identify the first case with serial next-generation sequencing (NGS) results that harboured a rare echinoderm microtubule associated protein like 4 gene (EML4) -ALK (breaking site at exon 19) fusion in a lung adenocarcinoma (LUAD) patient who acquired alectinib resistance rapidly (less than 3 months), followed by multi-drug resistance and short survival time.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Non-Small-Cell Lung; Exons; Humans; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Female; Humans; Lung Neoplasms; Middle Aged; Myositis; Piperidines; Protein Kinase Inhibitors

Topics: Adenocarcinoma of Lung; Carbazoles; Humans; Inhibitor of Apoptosis Proteins; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Receptor Protein-Tyrosine Kinases

Alectinib is an oral tyrosine kinase inhibitor currently recommended by the National Comprehensive Cancer Network (NCCN) as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase (ALK) gene rearrangement-positive non-small cell lung cancer (NSCLC). Skin toxicity is a known adverse effect of this medication, yet current recommendations are unclear regarding how to best manage patients who develop severe skin toxicity while taking alectinib.. Here, we describe a case of successful rechallenge with alectinib by utilizing a desensitization procedure in a patient who had developed severe alectinib-induced skin toxicity about two weeks into treatment.. Alectinib is currently recommended as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase gene rearrangement-positive NSCLC due to improved progression-free survival when compared to crizotinib. The development of skin toxicity can lead to early discontinuation of alectinib treatment, forcing providers and patients to select alternative, potentially less effective options. This case report provides evidence that patients who have experienced severe skin toxicity due to alectinib may be able to continue this first-line treatment option by rechallenging them using a desensitization procedure.

Topics: Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Carbazoles; Desensitization, Immunologic; Drug Hypersensitivity; Exanthema; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) have transformed the standard of care in lung cancer. A number of TKIs have been discovered that specifically target oncogenes, including MET receptor tyrosine kinase. Second-generation MET TKIs are showing improved efficacy over first-generation TKIs. Herein, we report a case of a patient with metastatic lung adenocarcinoma harboring a

Topics: Adenocarcinoma of Lung; Aged; B7-H1 Antigen; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Class I Phosphatidylinositol 3-Kinases; Exons; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridazines; Pyrimidines

Guidelines recommend testing for multiple biomarkers in non-small cell lung cancer (NSCLC) tumors. Blood-based liquid biopsy analyzing cell-free DNA (cfDNA) could be used in addition to tumor biopsy genotyping, especially if tissue/time are limiting.. To investigate the clinical utility of early cfDNA analysis (Guardant360® CDx) in treatment-naïve NSCLC patients.. A prospective cohort of treatment-naïve patients with metastatic NSCLC who underwent tumor and cfDNA analysis between 12/2018 and 2/2019 were included.. Ten patients were included: 6 males, median age 70.5 years (range 48-87), 8 prior smokers. Liquid biopsy was sent when cancer cells were detected in the biopsy specimen. Median time from diagnosis to receiving the report on the last biomarker from the tumor biopsy was 20 days (range 9-34); median time from blood draw to receiving the cfDNA findings was 9 days (range 7-12). The median difference between the cfDNA and the tumor analysis reports was 20 days (range 9-28). Actionable biomarkers were identified in four patients by both the biopsy analysis and the cfDNA analysis (2cases with EGFR mutations, one with ROS1 fusion, and one with EML4-ALK fusion for whom the biopsy analysis also identified an EGFR mutation not detected in the cfDNA analysis). Overall, eight patients received treatment (2 died before treatment initiation). Three patients received biomarker-based treatment (1 osimertinib, 1 alectinib, and 1 crizotinib).. These findings suggest that cfDNA analysis should be ordered by the pulmonologists early in the evaluation of patients with NSCLC, which might complement the tumor biopsy.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA, Neoplasm; Female; Genotyping Techniques; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Prospective Studies

There is still no clinically approved agent for mutant KRAS, which is the most common alteration in non-small-cell lung cancer (NSCLC). Flavopiridol is a semisynthetic flavonoid that inhibits cell growth through cyclin-dependent kinases in G1/S or G2/M of the cell cycle and induces apoptosis. In this study, we evaluated its effect on cellular apoptosis, survival, and metastasis mechanisms on KRAS mutant A549, Calu-1, and H2009 cell lines.. The cytotoxic effects of flavopiridol on NSCLC cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell viability test. The cells were treated with 200 and 400 nM flavopiridol, and, then, apoptosis, survival, and metastasis-related protein expressions were determined by Western blot analysis. The antimetastatic effects of flavopiridol were assessed by wound healing and Galectin-3 activity assay.. Flavopiridol drastically affected toxicity in all KRAS mutant NSCLC cells at nanomolar concentrations. Also, it could efficiently inhibit wound healing and Galectin-3 activity in all the cells tested. However, the metastasis-related protein expressions did not reflect these obvious effects on blotting. p-Erk was activated as a cellular survival mechanism to escape apoptosis in all the cells tested.. Although there are many mechanisms that still need to be elucidated, flavopiridol can be used as a metastasis inhibitor and an apoptosis inducer in KRAS mutant NSCLC.

Topics: A549 Cells; Adenocarcinoma of Lung; Apoptosis; Carcinoma, Non-Small-Cell Lung; Flavonoids; Humans; Lung Neoplasms; Mutation; Neoplasm Metastasis; Piperidines; Proto-Oncogene Proteins p21(ras)

Topics: Adenocarcinoma of Lung; Carbazoles; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Renal Dialysis; Safety

Transformation to small cell lung cancer is one phenomenon of acquired resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Few case reports have focused on other types of histological transformation. We report a case of transformation of ALK rearrangement-positive adenocarcinoma to NSCLC with neuroendocrine differentiation during alectinib therapy. A 36-year-old woman presented with a tumor in the left lower lobe and bone metastases. She was diagnosed with ALK rearrangement-positive adenocarcinoma by histopathology of the primary tumor. Alectinib had been effective for 8 months before new lesions appeared. Histopathological re-examination of a recurrent tumor revealed poorly differentiated carcinoma with insulinoma-associated protein 1 (INSM1) expression, which remained ALK-positive. Expression of CD133, BCL-2, and SOX2 was positive in comparison to the initial tumor. Expression of SOX2 became more strongly positive than it was before treatment. The immunohistochemical findings of these markers associated with cancer stem-like cells and/or neuroendocrine differentiation suggest that cancer stem cells play a role in the mechanisms of histological transformation and acquired resistance of ALK rearrangement-positive cancer. To our knowledge, this is the first report to suggest an association between cancer stem-like cells and histological transformation in ALK rearrangement-positive lung cancer.

Topics: Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Antigens, CD; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Transformation, Neoplastic; Female; Gene Rearrangement; Humans; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Repressor Proteins; SOXB1 Transcription Factors

Topics: Adenocarcinoma of Lung; Bevacizumab; Carbazoles; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors

Lung cancer remains the leading cause of cancer-related death worldwide. It is important to explore the biomarkers of diagnosis and prognosis in lung cancer. To evaluate the cytotoxicity of L-securinine and the expression and methylation of secreted frizzled-related proteins (SFRPs) genes in the human lung adenocarcinoma cells, cell counting kit-8 (CCK-8) assay was used to assess the proliferation of lung adenocarcinoma cells treated with L-securinine. Quantitative real-time PCR (qRT-PCR) and bisulfite sequencing PCR were used to detect the expression and the DNA methylation of SFRPs genes, respectively. L-securinine inhibited the proliferation of lung adenocarcinoma cells and induced the upregulation of SFRP1 gene expression and the methylation changes at CpG sites in the SFRP1 promoter region. L-securinine was a potential agent in the treatment of lung cancer by upregulation of SFRP1 gene expression and changing the SFRP1 gene methylation.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Azepines; Cell Line, Tumor; DNA Methylation; Heterocyclic Compounds, Bridged-Ring; Humans; Intracellular Signaling Peptides and Proteins; Lactones; Lung Neoplasms; Molecular Structure; Piperidines; Promoter Regions, Genetic; Proteins; Stereoisomerism

A 63-year-old woman with pulmonary adenocarcinoma (stage IIIB) that was positive for an epidermal growth factor receptor (EGFR) mutation and an anaplastic lymphoma kinase (ALK) rearrangement was treated with erlotinib as the first-line treatment, resulting in a stable disease. Due to skin rashes, fatigue and anorexia, erlotinib was suspended on erlotinib day 44. Alectinib was administered as the second-line treatment, exhibiting a partial response. On alectinib day 56, drug-induced lung injury forced suspension of alectinib, which was cured with corticosteroid therapy. ALK-tyrosine kinase inhibitors may be more effective for patients positive for both EGFR mutation and ALK rearrangement than other agents.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adrenal Cortex Hormones; Anaplastic Lymphoma Kinase; Carbazoles; Cough; ErbB Receptors; Erlotinib Hydrochloride; Female; Fever; Humans; Hypoxia; Lung Neoplasms; Middle Aged; Mutation; Piperidines; Receptor Protein-Tyrosine Kinases; Treatment Outcome

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Carbazoles; Female; Gene Fusion; Humans; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors

Overexpression of insulin growth factor 1 receptor (IGF-1R) and its ligand, insulin growth factor 1 (IGF-1), is related to treatment resistance and worse prognosis in many types of tumors. We reported recently that IGF-1R activation by IGF induces resistance to alectinib and stimulates the production of vascular endothelial growth factor, which indicates that IGF induces alectinib resistance and angiogenesis. This study aimed to determine the effect of bigeminal inhibition of anaplastic lymphoma kinase (ALK) and angiogenesis on human insulin growth factor 1 receptor (hIGF-1)-triggered drug resistance in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-positive lung cancer. Human lung adenocarcinoma H3122 and H2228 cells were exposed to a combination of insulin growth factor 1 receptor (IGF-1), alectinib, or apatinib. The effects of the combination therapy were examined using cell the Cell Counting Kit-8 assay, the colony-forming assay, the scratch test, and flow cytometry analysis, and the molecular mechanism was assessed by western blot. At nontoxic concentrations, apatinib restored alectinib sensitivity by increasing drug-induced apoptosis and inhibiting viability, migration, and invasion in IGF-triggered drug resistant cells. Moreover, we found that apatinib restored sensitivity to alectinib mainly through suppression of the ALK downstream signaling pathway and antiangiogenesis signaling. Taken together, our results indicate that simultaneous inhibition of ALK and vascular endothelial growth factor R2 by the combination of alectinib with apatinib may be useful for controlling progression of EML4-ALK fusion gene lung cancer by reversing ALK-TKI resistance and inhibiting angiogenesis.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Apoptosis; Carbazoles; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Humans; Insulin-Like Growth Factor I; Lung Neoplasms; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Pyridines; Receptor, IGF Type 1; Signal Transduction; Vascular Endothelial Growth Factor Receptor-2

Common gene fusion of the ALK gene is fusion of the ALK tyrosine kinase area and the 5'end of EML4. Seventeen EML4-ALK fusion variants have been reported. Herein, we report a novel EML4-ALK variant detected by next-generation sequencing in a 36-year-old female lung adenocarcinoma patient who experienced disease progression after six months of alectinib treatment. Second generation sequencing revealed an EML4-ALK fusion variant in which intron 19 of EML4 was fused to exon 20 of ALK. This is the first case of EML4-ALK (E19: A20) fusion to be reported. Alectinib may show unsatisfactory therapeutic effects for this kind of ALK fusion.

Topics: Adenocarcinoma of Lung; Carbazoles; Female; Humans; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors

A 36-year-old male was found two nodules in the right lower lobe of the lung. After the surgical resection, both lesions were diagnosed as invasive adenocarcinomas. One lesion was primarily lepidic growth component with EGFR-L858R mutation, and the other was micropapillary component with ALK translocation accompanying mediastinal lymphnode metastases. While he experienced disease recurrence, the disease was controlled by an ALK inhibitor, given based on the findings of surgical specimens. This is the first case who had two simultaneous lung cancers with EGFR mutation and ALK translocation in each respective lesion, and was successfully treated with ALK inhibitor at the post-surgical recurrence. J. Med. Invest. 64: 305-307, August, 2017.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adult; Anaplastic Lymphoma Kinase; Carbazoles; ErbB Receptors; Humans; Lung Neoplasms; Male; Mutation; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Translocation, Genetic

Alectinib is a second generation ALK inhibitor that has significant clinical activity in central nervous system (CNS) metastases in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Pseudoprogression (PsP) due to radiation necrosis during alecitnib treatment of central nervous system (CNS) metastases from ALK-rearranged NSCLC as been reported. Hence, distinguishing radiation-related PsP from alectinib-induced radiographic changes is important to avoid erroneous early trial discontinuation and abandonment of an effective treatment. However, it remains difficult to assess casuality of radiation necrosis is related to recent direct radiation or induced by alectinib treatment or both. It is also unknown how long from previous radiation can alectinib still induce radiation necrosis. Here we reported a crizotinib-refractory ALK-positive NSCLC patient who develop radiation necrosis in one of his metastatic CNS lesions after approximately 12 months of alectinib treatment who otherwise had on-going CNS response on alectinib. His most recent radiation to his CNS metastases was 7 years prior to the start of alectinib. This case illustrates that in the setting of pror CNS radiation, given the significant clinical activity of alectinib in CNS metastases in ALK-positive NSCLC patients the risk of CNS radiation necrosis remains long after previous radiation to the CNS metastases has been completed and can occur after durable response of treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Brain; Brain Neoplasms; Carbazoles; Crizotinib; Disease Progression; Humans; Lung Neoplasms; Male; Middle Aged; Necrosis; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiation Injuries; Receptor Protein-Tyrosine Kinases; Treatment Outcome

The new capability to generate mimicking chemical analogues and perform mass screenings of candidate drugs has been tested on B-cell receptor signalling, a driver of B-cell malignancies. These efforts have identified ibrutinib as a potent inhibitor of Bruton's tyrosine kinase. As the clinical use of ibrutinib increases, continued vigilant monitoring for rare adverse events is prudent, including the development of secondary malignancies. To date, the most common reported secondary malignancy is non-melanoma skin cancer; however, we present a case of secondary primary lung adenocarcinoma becoming clinically apparent shortly after initiating therapy with ibrutinib. Our patient had a sudden regression of the tumour with discontinuance of ibrutinib, and based on our understanding of paradoxical tumour growth caused by tyrosine kinase inhibitors it is our hypothesis that the complex multikinase activity of ibrutinib may stimulate tumour growth by targeting a subset of protein kinases critical for growth in some cancer cells.

Topics: Adenine; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Humans; Lung; Lung Neoplasms; Male; Piperidines; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed

Alectinib has been approved for the treatment of patients with anaplastic lymphoma kinase (ALK) gene rearrangement-positive advanced non-small cell lung cancer. In terms of adverse effects, the occurrence of a severe skin rash induced by alectinib is reportedly rare, compared with the occurrence of skin rash induced by epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). In the present case report, a 76-year-old woman with ALK-positive lung adenocarcinoma experienced disease progression after undergoing first-line chemotherapy. Subsequently, alectinib was administered as a second-line therapy. However, she discontinued alectinib therapy after 11days because of the occurrence of an alectinib-induced skin rash. Since the skin rash improved within one week, we attempted to perform oral desensitization to alectinib. The patient has not shown any recurrence of the rash or disease progression for 7 months since the successful oral desensitization to alectinib. Here, we describe the first case of successful oral desensitization against a skin rash induced by alectinib in a patient with ALK-positive lung adenocarcinoma. Desensitization to overcome adverse effects and to enable sustained treatment with alectinib should be considered in patients who develop alectinib sensitivities.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biopsy; Carbazoles; Desensitization, Immunologic; Exanthema; Female; Humans; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases

A 75-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged Stage IV lung adenocarcinoma was administered the selective anaplastic lymphoma kinase inhibitor, alectinib, as a third-line treatment in a Phase 1-2 study. On the 102nd day, chest computed tomography showed diffuse ground glass opacities. Laboratory data revealed high serum levels of KL-6, SP-D and lactate dehydrogenase without any clinical symptoms. There was no evidence of infection. Marked lymphocytosis was seen in bronchoalveolar lavage fluid analysis, and transbronchial lung biopsy showed mild thickening of alveolar septa and lymphocyte infiltration. Interstitial lung disease was judged to be related to alectinib based on improvements in imaging findings and serum biomarkers after discontinuation of alectinib. To our knowledge, this is the first reported case of alectinib-induced interstitial lung disease. Alectinib is a promising drug for ALK-rearranged non-small cell lung cancer. Clinical trials of this selective anaplastic lymphoma kinase inhibitor will facilitate the meticulous elucidation of its long-term safety profile.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Bronchoalveolar Lavage Fluid; Carbazoles; Female; Humans; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Piperidines; Protein Kinase Inhibitors; Receptor Protein-Tyrosine Kinases; Tomography, X-Ray Computed

To understand the heterogeneous behaviors of individual cancer cells, it is essential to investigate gene expression levels as well as their divergence between different individual cells. Recent advances in next-generation sequencing-related technologies have enabled us to conduct a single-cell RNA-Seq analysis of a series of lung adenocarcinoma cell lines.. We analyze a total of 336 single-cell RNA-Seq libraries from seven cell lines. The results are highly robust regarding both average expression levels and the relative gene expression differences between individual cells. Gene expression diversity is characteristic depending on genes and pathways. Analyses of individual cells treated with the multi-tyrosine kinase inhibitor vandetanib reveal that, while the ribosomal genes and many other so-called house-keeping genes reduce their relative expression diversity during the drug treatment, the genes that are directly targeted by vandetanib, the EGFR and RET genes, remain constant. Rigid transcriptional control of these genes may not allow plastic changes of their expression with the drug treatment or during the cellular acquisition of drug resistance. Additionally, we find that the gene expression patterns of cancer-related genes are sometimes more diverse than expected based on the founder cells. Furthermore, we find that this diversity is occasionally latent in a normal state and initially becomes apparent after the drug treatment.. Characteristic patterns in gene expression divergence, which would not be revealed by transcriptome analysis of bulk cells, may also play important roles when cells acquire drug resistance, perhaps by providing a cellular reservoir for gene expression programs.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Cell Line, Tumor; Cytoskeletal Proteins; Drug Delivery Systems; ErbB Receptors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, Essential; Humans; Lung Neoplasms; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Quinazolines; RNA; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome

Alectinib, the second generation anaplastic lymphoma kinase (ALK) inhibitor, has significant potency in patients with ALK rearrangement positive non-small cell lung cancer (NSCLC), and its toxicity is generally well tolerable. We report a patient who developed severe acute interstitial lung disease after alectinib treatment. An 86-year-old woman with stage IV lung adenocarcinoma positive for rearrangement of ALK gene was treated with alectinib. On the 215th day after initiation of alectinib administration, she was admitted to our hospital with the symptom of progressive dyspnea. Computed tomography (CT) revealed diffuse ground glass opacities and consolidations in both lungs, and analysis of bronchoalveolar lavage fluid revealed pronounced lymphocytosis. There was no evidence of infection or other specific causes of her condition, and she was therefore diagnosed with interstitial lung disease induced by alectinib. Her CT findings and respiratory condition improved after steroid pulse therapy. As far as we are aware, this is the first reported case of alectinib-induced severe interstitial lung disease (ILD). We should be aware of the possibility of such a severe adverse event and should therefore carefully monitor patients treated with this drug.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Adrenal Cortex Hormones; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Piperidines; Receptor Protein-Tyrosine Kinases

We herein report a case of a 46-year-old woman with anaplastic lymphoma kinase (ALK)-rearranged stage IV lung adenocarcinoma who received the ALK inhibitor crizotinib as second-line therapy. On the 47th day following crizotinib initiation, a chest computed tomography scan revealed ground-glass opacities with a clinical manifestation of desaturation, although a partial response to treatment was detected. The diagnosis of crizotinib-induced interstitial lung disease (ILD) was confirmed, and crizotinib was discontinued, followed by the initiation of corticosteroid therapy. After improvement of ILD with corticosteroid therapy, alectinib was administered as salvage therapy, resulting in tumor shrinkage without any recurrence of ILD. To the best of our knowledge, this is the first report of successful alectinib treatment following crizotinib-induced ILD. Our results indicate that alectinib could be a promising alternative treatment option in patients with crizotinib-induced ILD.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Carbazoles; Crizotinib; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Radiography, Thoracic; Tomography, X-Ray Computed; Treatment Outcome

Oncogenic fusion of the RET (rearranged during transfection) gene was recently identified as a novel driver gene aberration not only for the development of thyroid carcinoma but also of lung adenocarcinoma, the most frequent histological type of lung cancer. This study constructed and analyzed transgenic mice expressing KIF5B-RET, the predominant form of RET fusion gene specific for lung adenocarcinoma, under the control of the SPC (surfactant protein C) gene promoter. The mice expressed the KIF5B-RET fusion gene specifically in lung alveolar epithelial cells, and developed multiple tumors in the lungs. Treatment of the transgenic mice with vandetanib, which is a RET tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration for the treatment of thyroid carcinoma, for 8 or 20 weeks led to a marked reduction in the number of lung tumors (3.3 versus 0 and 6.5 versus 0.2 per tissue section, respectively; P < 0.01, t-test). The results suggest that the RET fusion functions as a driver for the development of lung tumors, whose growth is inhibited by RET tyrosine kinase inhibitors.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Carcinogenesis; Humans; Lung Neoplasms; Mice; Mice, Transgenic; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Quinazolines

Rearrangements of the proto-oncogene RET are newly identified potential driver mutations in lung adenocarcinoma (LAD). However, the absence of cell lines harboring RET fusion genes has hampered the investigation of the biological relevance of RET and the development of RET-targeted therapy. Thus, we aimed to identify a RET fusion positive LAD cell line. Eleven LAD cell lines were screened for RET fusion transcripts by reverse transcription-polymerase chain reaction. The biological relevance of the CCDC6-RET gene products was assessed by cell growth, survival and phosphorylation of ERK1/2 and AKT with or without the suppression of RET expression using RNA interference. The efficacy of RET inhibitors was evaluated in vitro using a culture system and in an in vivo xenograft model. Expression of the CCDC6-RET fusion gene in LC-2/ad cells was demonstrated by the mRNA and protein levels, and the genomic break-point was confirmed by genomic DNA sequencing. Mutations in KRAS and EGFR were not observed in the LC-2/ad cells. CCDC6-RET was constitutively active, and the introduction of a siRNA targeting the RET 3' region decreased cell proliferation by downregulating RET and ERK1/2 phosphorylation. Moreover, treatment with RET-inhibitors, including vandetanib, reduced cell viability, which was accompanied by the downregulation of the AKT and ERK1/2 signaling pathways. Vandetanib exhibited anti-tumor effects in the xenograft model. Endogenously expressing CCDC6-RET contributed to cell growth. The inhibition of kinase activity could be an effective treatment strategy for LAD. LC-2/ad is a useful model for developing fusion RET-targeted therapy.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cytoskeletal Proteins; Down-Regulation; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mice; Mice, Nude; Mutation; Phosphorylation; Piperidines; Proto-Oncogene Mas; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-ret; Quinazolines; RNA, Messenger; Signal Transduction; Transcriptome

Through an integrated molecular- and histopathology-based screening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion-positive and 13 ROS1-fusion-positive adenocarcinomas, including for unidentified fusion partners for ROS1. In addition, we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas. A multivariate analysis of 1,116 adenocarcinomas containing these 71 kinase-fusion-positive adenocarcinomas identified four independent factors that are indicators of poor prognosis: age ≥ 50 years, male sex, high pathological stage and negative kinase-fusion status.

Topics: 3T3 Cells; Adenocarcinoma; Adenocarcinoma of Lung; Adult; Age Factors; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Animals; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cytoskeletal Proteins; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Mice; Middle Aged; Neoplasm Staging; Oncogene Proteins, Fusion; Piperidines; Prognosis; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Quinazolines; Receptor Protein-Tyrosine Kinases; Sex Factors

We identified in-frame fusion transcripts of KIF5B (the kinesin family 5B gene) and the RET oncogene, which are present in 1-2% of lung adenocarcinomas (LADCs) from people from Japan and the United States, using whole-transcriptome sequencing. The KIF5B-RET fusion leads to aberrant activation of RET kinase and is considered to be a new driver mutation of LADC because it segregates from mutations or fusions in EGFR, KRAS, HER2 and ALK, and a RET tyrosine kinase inhibitor, vandetanib, suppresses the fusion-induced anchorage-independent growth activity of NIH3T3 cells.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Animals; Cell Transformation, Neoplastic; ErbB Receptors; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; Humans; Japan; Kinesins; Lung Neoplasms; Mice; NIH 3T3 Cells; Norway; Oncogene Proteins, Fusion; Piperidines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Quinazolines; ras Proteins; Receptor Protein-Tyrosine Kinases; Receptor, ErbB-2; United States

To study the molecular mechanisms regulating cancer cell resistance to four different tyrosine kinase inhibitors (TKIs): erlotinib, gefitinib, vandetanib and sorafenib.. An in vitro model of acquired resistance to these TKIs was developed by continuously treating the human lung adenocarcinoma cell line CALU-3 with escalating doses of each drug. Transcriptional profiling was performed with Agilent whole genome microarrays. Western blot analysis, enzyme-linked immunosorbent (ELISA), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation, migration, invasion and anchorage-independent colony growth assays were conducted in vitro and experiments with established xenografts in athymic nude mice were performed in vivo in parental (P) and TKI-resistant (R) CALU-3 cell lines.. As compared with P-CALU-3 cells, in TKI-R CALU-3 cell lines a significant increase in the expression of activated, phosphorylated MET, IGF-1R, AKT, MEK, MAPK and of survivin was observed. Downregulation of E-cadherin and amphiregulin mRNAs and upregulation of vimentin, VE-cadherin, HIF-1α and vascular endothelial growth factor receptor-1 mRNAs were observed in all four TKI-R CALU-3 cell lines. All four TKI-R CALU-3 cells showed increased invasion, migration and anchorage-independent growth. Together, these data suggest epithelial to mesenchymal transition (EMT) in TKI-R CALU-3 cells. Treatment with several agents that target AKT, MET or IGF-1R did not affect TKI-R CALU-3 cell proliferation. In contrast, treatment with MSC19363669B and selumetinib, two selective MEK inhibitors, caused inhibition of cell proliferation, invasion, migration, anchorage-independent growth in vitro and of tumour growth in vivo of all four TKI-R CALU-3 cell lines.. These data suggest that resistance to four different TKIs is characterised by EMT, which is MEK-inhibitor sensitive in human CALU-3 lung adenocarcinoma.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Benzenesulfonates; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Erlotinib Hydrochloride; Gefitinib; Gene Expression Profiling; Humans; Lung Neoplasms; MAP Kinase Kinase Kinases; Mice; Mice, Nude; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Sorafenib; Xenograft Model Antitumor Assays

No clinically effective chemoprevention for lung cancer has been found. Angiogenesis is an early feature of both adenocarcinoma and squamous cell lung cancer. We investigated the effects of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) inhibition on lung carcinogenesis in a murine model of adenocarcinoma. The VEGFR-2 tyrosine kinase inhibitor, vandetanib, was given to FVB/N mice in chow for 7 days at varying doses to show pharmacologic activity by inhibition of VEGF-mediated VEFGR-2 and ERK phosphorylation. Plasma levels corroborated adequate dosage. For chemoprevention experiments, mice were injected i.p. with 1 mg/g of urethane, a carcinogen found in tobacco smoke. Chow containing vandetanib, 75 mg/kg/d, or control chow was given to mice, starting 7 days after urethane administration. Sixteen weeks after urethane injection, mice were sacrificed, tumors enumerated and measured. Vandetanib resulted in reductions in tumor multiplicity (6.5 +/- 0.86 versus 1.0 +/- 0.30, P = 0.001) and average tumor volume (0.85 +/- 0.10 versus 0.15 +/- 0.09 mm(3), P = 0.001), but not incidence (71% versus 100%, P = ns), compared with control. As vandetanib has other activities besides VEGFR-2 tyrosine kinase inhibition, we gave the anti-VEGFR-2 monoclonal antibody, DC101, for weeks 11 to 15 of a urethane carcinogenesis protocol with an arrest in tumor volume increase, but no change in multiplicity or incidence. Further investigation of the chemopreventive effect of vandetanib and other VEGF signaling inhibitors is needed.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Carcinogens; Chemoprevention; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Mice; Molecular Targeted Therapy; Neovascularization, Pathologic; Piperidines; Protein Kinase Inhibitors; Quinazolines; Urethane; Vascular Endothelial Growth Factor Receptor-2