RRC ID 50056
著者 Uchibori K, Inase N, Araki M, Kamada M, Sato S, Okuno Y, Fujita N, Katayama R.
タイトル Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer.
ジャーナル Nat Commun
Abstract 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.
巻・号 8
ページ 14768
公開日 2017-3-13
DOI 10.1038/ncomms14768
PII ncomms14768
PMID 28287083
PMC PMC5355811
MeSH Acrylamides Aniline Compounds Animals Antibodies, Monoclonal / pharmacology* Antineoplastic Agents / pharmacology* Antineoplastic Combined Chemotherapy Protocols Carcinoma, Non-Small-Cell Lung / drug therapy* Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / mortality Carcinoma, Non-Small-Cell Lung / pathology Cell Line, Tumor Cetuximab / chemistry Cetuximab / pharmacology* Drug Resistance, Neoplasm ErbB Receptors / antagonists & inhibitors ErbB Receptors / chemistry ErbB Receptors / genetics ErbB Receptors / metabolism Gene Expression Humans Lung Neoplasms / drug therapy* Lung Neoplasms / genetics Lung Neoplasms / mortality Lung Neoplasms / pathology Mice Mice, Nude Molecular Dynamics Simulation Mutation Organophosphorus Compounds / chemistry Organophosphorus Compounds / pharmacology* Panitumumab Piperazines / pharmacology Protein Kinase Inhibitors / pharmacology* Pyrimidines / chemistry Pyrimidines / pharmacology* Survival Analysis Tumor Burden / drug effects Xenograft Model Antitumor Assays
IF 12.121
引用数 126
リソース情報
遺伝子材料 pENTER-EGFR wild-type (RDB15488) pENTER-EGFR Del19 (RDB15489) pENTER-EGFR T790M/del19 (RDB15490) pENTER-EGFR C797S/del19 (RDB15491) pENTER-EGFR C797S/T790M/del19 (RDB15492) pENTER-EGFR L858R (RDB15493) pENTER-EGFR T790M/L858R (RDB15494) pENTER-EGFR C797S/L858R (RDB15495) pENTER-EGFR C797S/T790M/L858R (RDB15496).