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

doi:10.1371/journal.pone.0084700

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

PLoS One. 2013 Dec 26;8(12):e84700. doi: 10.1371/journal.pone.0084700. eCollection 2013.

Affiliations

¹ Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
² Laboratory of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
³ Division of Tumor Dynamics and Regulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.

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 EGFR-T790M 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acrylamides / pharmacology*
Afatinib
Amino Acid Substitution
Animals
Cell Line, Tumor
Crizotinib
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / genetics
ErbB Receptors / metabolism
Female
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Mice
Mice, SCID
Mutation, Missense
Phosphorylation
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / genetics
Proto-Oncogene Proteins c-met / metabolism
Pyrazoles / pharmacology*
Pyridines / pharmacology*
Pyrimidines / pharmacology*
Quinazolines
Xenograft Model Antitumor Assays

Substances

Acrylamides
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Pyrimidines
Quinazolines
Afatinib
Crizotinib
WZ4002
EGFR protein, human
ErbB Receptors
MET protein, human
Proto-Oncogene Proteins c-met

Grants and funding

This study was supported by KAKENHI (Grants-in-Aid for Scientific Research on Innovative Areas "Integrative Research on Cancer Microenvironment Network" (to SY) and Grant-in-Aid for Young Scientists [to TY and ST]), and Grants-in-Aid for Project for Development of Innovative Research on Cancer Therapeutics (P-Direct) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.