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.

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

Grant support

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.