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

Ken Uchibori, Naohiko Inase, Mitsugu Araki, Mayumi Kamada, Shigeo Sato, Yasushi Okuno, Naoya Fujita and Ryohei Katayama ()
Additional contact information
Ken Uchibori: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
Naohiko Inase: Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
Mitsugu Araki: RIKEN Advanced Institute for Computational Science
Mayumi Kamada: Graduate School of Medicine, Kyoto University
Shigeo Sato: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
Yasushi Okuno: RIKEN Advanced Institute for Computational Science
Naoya Fujita: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research
Ryohei Katayama: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms14768 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14768

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms14768

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().