Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors

Shigeki Nanjo, Tadaaki Yamada, Hiroshi Nishihara, Shinji Takeuchi, Takako Sano, Takayuki Nakagawa, Daisuke Ishikawa, Lu Zhao, Hiromichi Ebi, Kazuo Yasumoto, Kunio Matsumoto, Seiji Yano

研究成果: Article

35 引用 (Scopus)

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Purpose: Although EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have shown dramatic effects against EGFR mutant lung cancer, patients ultimately develop resistance by multiple mechanisms. We therefore assessed the ability of combined treatment with the Met inhibitor crizotinib and new generation EGFR-TKIs to overcome resistance to first-generation EGFR-TKIs. Experimental Design: Lung cancer cell lines made resistant to EGFR-TKIs by the gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression and mice with tumors induced by these cells were treated with crizotinib and a new generation EGFR-TKI. Results: The new generation EGFR-TKI inhibited the growth of lung cancer cells containing the gatekeeper EGFRT790M mutation, but did not inhibit the growth of cells with Met amplification or HGF overexpression. In contrast, combined therapy with crizotinib plus afatinib or WZ4002 was effective against all three types of cells, inhibiting EGFR and Met phosphorylation and their downstream molecules. Crizotinib combined with afatinib or WZ4002 potently inhibited the growth of mouse tumors induced by these lung cancer cell lines. However, the combination of high dose crizotinib and afatinib, but not WZ4002, triggered severe adverse events. Conclusions: Our results suggest that the dual blockade of mutant EGFR and Met by crizotinib and a new generation EGFR-TKI may be promising for overcoming resistance to reversible EGFR-TKIs but careful assessment is warranted clinically.

元の言語English
記事番号0084700
ジャーナルPloS one
8
発行部数12
DOI
出版物ステータスPublished - 2013 12 26

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

これを引用

Nanjo, S., Yamada, T., Nishihara, H., Takeuchi, S., Sano, T., Nakagawa, T., Ishikawa, D., Zhao, L., Ebi, H., Yasumoto, K., Matsumoto, K., & Yano, S. (2013). Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors. PloS one, 8(12), [0084700]. https://doi.org/10.1371/journal.pone.0084700