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

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number0084700
JournalPloS one
Volume8
Issue number12
DOIs
Publication statusPublished - 2013 Dec 26
Externally publishedYes

Fingerprint

lung neoplasms
tyrosine
phosphotransferases (kinases)
Phosphotransferases
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Lung Neoplasms
Cells
cell lines
mutation
mutants
neoplasms
Amplification
Tumors
mice
Cell Line
cell growth
Growth Inhibitors
phosphorylation
Mutation

ASJC Scopus subject areas

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

Cite this

Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors. / Nanjo, Shigeki; Yamada, Tadaaki; Nishihara, Hiroshi; Takeuchi, Shinji; Sano, Takako; Nakagawa, Takayuki; Ishikawa, Daisuke; Zhao, Lu; Ebi, Hiromichi; Yasumoto, Kazuo; Matsumoto, Kunio; Yano, Seiji.

In: PloS one, Vol. 8, No. 12, 0084700, 26.12.2013.

Research output: Contribution to journalArticle

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, vol. 8, no. 12, 0084700. https://doi.org/10.1371/journal.pone.0084700
Nanjo, Shigeki ; Yamada, Tadaaki ; Nishihara, Hiroshi ; Takeuchi, Shinji ; Sano, Takako ; Nakagawa, Takayuki ; Ishikawa, Daisuke ; Zhao, Lu ; Ebi, Hiromichi ; Yasumoto, Kazuo ; Matsumoto, Kunio ; Yano, Seiji. / Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors. In: PloS one. 2013 ; Vol. 8, No. 12.
@article{4ada2b2faed344428cf3bb86cf161953,
title = "Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors",
abstract = "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.",
author = "Shigeki Nanjo and Tadaaki Yamada and Hiroshi Nishihara and Shinji Takeuchi and Takako Sano and Takayuki Nakagawa and Daisuke Ishikawa and Lu Zhao and Hiromichi Ebi and Kazuo Yasumoto and Kunio Matsumoto and Seiji Yano",
year = "2013",
month = "12",
day = "26",
doi = "10.1371/journal.pone.0084700",
language = "English",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - Ability of the Met kinase inhibitor crizotinib and new generation EGFR inhibitors to overcome resistance to EGFR inhibitors

AU - Nanjo, Shigeki

AU - Yamada, Tadaaki

AU - Nishihara, Hiroshi

AU - Takeuchi, Shinji

AU - Sano, Takako

AU - Nakagawa, Takayuki

AU - Ishikawa, Daisuke

AU - Zhao, Lu

AU - Ebi, Hiromichi

AU - Yasumoto, Kazuo

AU - Matsumoto, Kunio

AU - Yano, Seiji

PY - 2013/12/26

Y1 - 2013/12/26

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84891333707&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891333707&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0084700

DO - 10.1371/journal.pone.0084700

M3 - Article

C2 - 24386407

AN - SCOPUS:84891333707

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 12

M1 - 0084700

ER -