Amplification of EGFR Wild-Type Alleles in Non-Small Cell Lung Cancer Cells Confers Acquired Resistance to Mutation-Selective EGFR Tyrosine Kinase Inhibitors

作者：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^*

来源：Cancer Research, 2017, 77(8): 2078-2089.

DOI：10.1158/0008-5472.CAN-16-2359

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.

• 出版日期2017-4-15