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

Authors :
Ryohei Katayama
Naohiko Inase
Ken Uchibori
Yasushi Okuno
Mitsugu Araki
Mayumi Kamada
Shigeo Sato
Naoya Fujita
Source :
Nature Communications, Vol 8, Iss 1, Pp 1-16 (2017), Nature Communications
Publication Year :
2017
Publisher :
Nature Portfolio, 2017.

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.<br />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.

Details

Language :
English
ISSN :
20411723
Volume :
8
Issue :
1
Database :
OpenAIRE
Journal :
Nature Communications
Accession number :
edsair.doi.dedup.....a4f1dd6b5563fa2ad508d337f7273a95