Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer
| العنوان: | Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer |
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| المؤلفون: | Ryohei Katayama, Naohiko Inase, Ken Uchibori, Yasushi Okuno, Mitsugu Araki, Mayumi Kamada, Shigeo Sato, Naoya Fujita |
| المصدر: | Nature Communications, Vol 8, Iss 1, Pp 1-16 (2017) Nature Communications |
| بيانات النشر: | Nature Portfolio, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Lung Neoplasms, Cetuximab, Gene Expression, General Physics and Astronomy, Pharmacology, Piperazines, Mice, T790M, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Osimertinib, Epidermal growth factor receptor, Aniline Compounds, Multidisciplinary, biology, Chemistry, Kinase, Panitumumab, Antibodies, Monoclonal, Tumor Burden, ErbB Receptors, 030220 oncology & carcinogenesis, medicine.drug, Combination therapy, Brigatinib, Science, Mice, Nude, Antineoplastic Agents, Molecular Dynamics Simulation, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Organophosphorus Compounds, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Protein Kinase Inhibitors, Acrylamides, General Chemistry, Survival Analysis, Xenograft Model Antitumor Assays, respiratory tract diseases, Pyrimidines, 030104 developmental biology, Drug Resistance, Neoplasm, Mutation, biology.protein |
| الوصف: | Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR–tyrosine kinase inhibitors (EGFR–TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR–TKI resistance. In the present study, we identify brigatinib to be effective against triple-mutation-harbouring cells in vitro and in vivo. Our original computational simulation demonstrates that brigatinib fits into the ATP-binding pocket of triple-mutant EGFR. The structure–activity relationship analysis reveals the key component in brigatinib to inhibit the triple-mutant EGFR. The efficacy of brigatinib is enhanced markedly by combination with anti-EGFR antibody because of the decrease of surface and total EGFR expression. Thus, the combination therapy of brigatinib with anti-EGFR antibody is a powerful candidate to overcome triple-mutant EGFR. EGFR変異陽性肺がんに対する新規耐性克服療法を発見 --今後予想されるオシメルチニブ耐性の克服へ--. 京都大学プレスリリース. 2017-04-03. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a4f1dd6b5563fa2ad508d337f7273a95Test https://doaj.org/article/7e03180accc34d52b7997deb52cfee5fTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a4f1dd6b5563fa2ad508d337f7273a95 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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