Overcoming resistance by ALK compound mutation (I1171S + G1269A) after sequential treatment of multiple ALK inhibitors in non‐small cell lung cancer
| العنوان: | Overcoming resistance by ALK compound mutation (I1171S + G1269A) after sequential treatment of multiple ALK inhibitors in non‐small cell lung cancer |
|---|---|
| المؤلفون: | Mika Tsukahara, Koutaroh Okada, Ryohei Katayama, Noriko Yanagitani, Makoto Nishio, Kenichi Okubo, Ken Uchibori, Ken Takahashi, Yosuke Seto, Naoya Fujita, Shinya Uematsu, Tomoko Oh-hara |
| المصدر: | Thoracic Cancer, Vol 11, Iss 3, Pp 581-587 (2020) Thoracic Cancer |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Alectinib, Lung Neoplasms, Apoptosis, next‐generation sequence, 0302 clinical medicine, Piperidines, Carcinoma, Non-Small-Cell Lung, hemic and lymphatic diseases, Tumor Cells, Cultured, Anaplastic lymphoma kinase, Medicine, Anaplastic Lymphoma Kinase, Sulfones, ALK compound mutation, Sanger sequencing, General Medicine, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Oncology, 030220 oncology & carcinogenesis, symbols, Original Article, Female, medicine.drug, Pulmonary and Respiratory Medicine, non‐small cell lung cancer, Brigatinib, Carbazoles, lcsh:RC254-282, 03 medical and health sciences, symbols.namesake, Organophosphorus Compounds, Crizotinib, Humans, Lung cancer, Protein Kinase Inhibitors, Aged, Cell Proliferation, Ceritinib, business.industry, Original Articles, medicine.disease, Lorlatinib, 030104 developmental biology, Pyrimidines, Drug Resistance, Neoplasm, Mutation, Cancer research, business |
| الوصف: | Background Anaplastic lymphoma kinase (ALK) fusion genes are found in 3%-5% of non-small cell lung cancers (NSCLCs). ALK inhibitors show a very high response rate to ALK-positive NSCLCs. However, the emergence of acquired resistance is inevitable. In this study, we investigated the drugs for overcoming resistance especially compound mutations after sequential treatment with crizotinib, alectinib, and lorlatinib. Method Next-generation sequencing (NGS) and Sanger sequencing were performed on a liver biopsy tissue obtained from a clinical case. Ba/F3 cells in which mutant EML4-ALK were overexpressed were prepared, and cell viability assay and immunoblotting were performed to check the sensitivity of five independent ALK inhibitors. Results I1171S + G1269A double mutation was identified by NGS and Sanger sequencing on a liver biopsy tissue from a patient who relapsed on lorlatinib treatment. Ceritinib and brigatinib-but not other ALK inhibitors-were active against the compound mutations in the cell line model. Conclusions With the sequential ALK inhibitors treatment, cancer cells accumulate new mutations in addition to mutations acquired previously. The identified compound mutation (I1171S + G1269A) was found to be sensitive to ceritinib and brigatinib, and indeed the patient's tumor partially responded to ceritinib. Key points ALK compound mutation was found in a clinical sample that was resistant to lorlatinib after sequential ALK-tyrosine kinase inhibitor (TKI) treatment. Ceritinib and brigatinib are potential overcoming drugs against ALK I1171S + G1269A double mutation. |
| اللغة: | English |
| تدمد: | 1759-7706 1759-7714 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::435113d9a070a711eacc79dd3055f9b4Test https://doaj.org/article/8eb722c532b94cce883b69c0048498a1Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....435113d9a070a711eacc79dd3055f9b4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17597706 17597714 |
|---|