MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer

J Hematol Oncol. 2019 Jun 21;12(1):63. doi: 10.1186/s13045-019-0759-9.

Abstract

Treatment of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutation with EGFR-TKIs has achieved great success, yet faces the development of acquired resistance as the major obstacle to long-term disease remission in the clinic. MET (or c-MET) gene amplification has long been known as an important resistance mechanism to first- or second-generation EGFR-TKIs in addition to the appearance of T790 M mutation. Recent preclinical and clinical studies have suggested that MET amplification and/or protein hyperactivation is likely to be a key mechanism underlying acquired resistance to third-generation EGFR-TKIs such as osimertinib as well, particularly when used as a first-line therapy. EGFR-mutant NSCLCs that have relapsed from first-generation EGFR-TKI treatment and have MET amplification and/or protein hyperactivation should be insensitive to osimertinib monotherapy. Therefore, combinatorial therapy with osimertinib and a MET or even a MEK inhibitor should be considered for these patients with resistant NSCLC carrying MET amplification and/or protein hyperactivation.

Publication types

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

MeSH terms

  • Acrylamides / pharmacology
  • Acrylamides / therapeutic use
  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Drug Resistance, Neoplasm
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Molecular Targeted Therapy
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / genetics

Substances

  • Acrylamides
  • Aniline Compounds
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • osimertinib
  • EGFR protein, human
  • ErbB Receptors
  • Proto-Oncogene Proteins c-met