Amplification of EGFR wild-type alleles in non-small cell lung cancer cells confers acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors

Shigenari Nukaga, Hiroyuki Yasuda, Katsuya Tsuchihara, Junko Hamamoto, Keita Masuzawa, Ichiro Kawada, Katsuhiko Naoki, Shingo Matsumoto, Sachiyo Mimaki, Shinnosuke Ikemura, Koichi Goto, Tomoko Betsuyaku, Kenzo Soejima

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

EGFR-mutated lung cancers account for a significant subgroup of non-small cell lung cancers overall. Third-generation EGFR tyrosine kinase inhibitors (TKI) are mutation-selective inhibitors with minimal effects on wild-typeEGFR. Acquired resistance develops to these agents, however, the mechanisms are as yet uncharacterized. In this study, we report that the Src-AKT pathway contributes to acquired resistance to these TKI. In addition, amplification of EGFR wild-type alleles but not mutant alleles was sufficient to confer acquired resistance. These findings underscore the importance of signals from wild-type EGFR alleles in acquiring resistance to mutant-selective EGFR-TKI. Our data provide evidence of wildtype allele-mediated resistance, a novel concept of acquired resistance in response to mutation-selective inhibitor therapy in cancer treatment.

Original languageEnglish
Pages (from-to)2078-2089
Number of pages12
JournalCancer Research
Volume77
Issue number8
DOIs
Publication statusPublished - 2017 Apr 15

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Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Alleles
Mutation
Lung Neoplasms
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Amplification of EGFR wild-type alleles in non-small cell lung cancer cells confers acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors. / Nukaga, Shigenari; Yasuda, Hiroyuki; Tsuchihara, Katsuya; Hamamoto, Junko; Masuzawa, Keita; Kawada, Ichiro; Naoki, Katsuhiko; Matsumoto, Shingo; Mimaki, Sachiyo; Ikemura, Shinnosuke; Goto, Koichi; Betsuyaku, Tomoko; Soejima, Kenzo.

In: Cancer Research, Vol. 77, No. 8, 15.04.2017, p. 2078-2089.

Research output: Contribution to journalArticle

Nukaga, Shigenari ; Yasuda, Hiroyuki ; Tsuchihara, Katsuya ; Hamamoto, Junko ; Masuzawa, Keita ; Kawada, Ichiro ; Naoki, Katsuhiko ; Matsumoto, Shingo ; Mimaki, Sachiyo ; Ikemura, Shinnosuke ; Goto, Koichi ; Betsuyaku, Tomoko ; Soejima, Kenzo. / Amplification of EGFR wild-type alleles in non-small cell lung cancer cells confers acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors. In: Cancer Research. 2017 ; Vol. 77, No. 8. pp. 2078-2089.
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AU - Kawada, Ichiro

AU - Naoki, Katsuhiko

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