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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Published in:Nature communications Vol. 8; no. 1; p. 14768
Main Authors: Uchibori, Ken, Inase, Naohiko, Araki, Mitsugu, Kamada, Mayumi, Sato, Shigeo, Okuno, Yasushi, Fujita, Naoya, Katayama, Ryohei
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 13.03.2017
Nature Publishing Group
Nature Portfolio
Subjects:
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
Online Access:Get full text
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Summary: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.
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ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms14768