RRC ID 50056
Author Uchibori K, Inase N, Araki M, Kamada M, Sato S, Okuno Y, Fujita N, Katayama R.
Title Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer.
Journal 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.
Volume 8
Pages 14768
Published 2017-3-13
DOI 10.1038/ncomms14768
PII ncomms14768
PMID 28287083
PMC PMC5355811
IF 12.353
DNA material 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).