Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer

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 posi...

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Veröffentlicht in:	Nature communications Jg. 8; H. 1; S. 14768
Hauptverfasser:	Uchibori, Ken, Inase, Naohiko, Araki, Mitsugu, Kamada, Mayumi, Sato, Shigeo, Okuno, Yasushi, Fujita, Naoya, Katayama, Ryohei
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 13.03.2017 Nature Publishing Group Nature Portfolio
Schlagworte:	13/31 13/95 38/109 631/67/1059/2326 631/67/1612/1350 64/60 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 Humanities and Social Sciences Humans Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - mortality Lung Neoplasms - pathology Mice Mice, Nude Molecular Dynamics Simulation multidisciplinary Mutation Organophosphorus Compounds - chemistry Organophosphorus Compounds - pharmacology Panitumumab Piperazines - pharmacology Protein Kinase Inhibitors - pharmacology Pyrimidines - chemistry Pyrimidines - pharmacology Science Science (multidisciplinary) Survival Analysis Tumor Burden - drug effects Xenograft Model Antitumor Assays
ISSN:	2041-1723, 2041-1723
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Zusammenfassung:	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. Resistance to EGFR-tyrosine kinase inhibitors in non-small-cell lung cancer is mediated by the C797S/T790M/activating mutation. Here, the authors identify brigatinib as a potential drug that in combination with anti-EGFR can overcome resistance in mutated cells.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms14768