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MET inhibitors in combination with other therapies in non-small cell lung cancer

Sukhmani Padda1, Joel W Neal1, Heather A Wakelee1

  • 1Stanford University/Stanford Cancer Institute, 875 Blake Wilbur Drive, Stanford, CA 94305-5826, USA.

Translational Lung Cancer Research
|March 26, 2015
PubMed

Insights

MET inhibitors, including small molecules and antibodies, show promise in treating non-small cell lung cancer (NSCLC). These therapies can overcome tumor resistance to EGFR inhibitors and improve patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • MET signaling, driven by hepatocyte growth factor/scatter factor (HGF), promotes tumor growth, invasion, and angiogenesis.
  • MET alterations are implicated in non-small cell lung cancer (NSCLC) aggressiveness and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).

Purpose of the Study:

  • To review MET inhibitors, their mechanisms of action, and their potential in combination therapies for lung cancer.
  • To discuss how MET inhibition can overcome resistance to EGFR TKIs and improve prognostic outcomes in NSCLC.

Main Methods:

  • Review of small molecule MET inhibitors targeting the intracellular tyrosine kinase domain (e.g., tivantinib, cabozantinib, crizotinib).
  • Discussion of the monoclonal antibody fragment onartuzumab (MetMAb) that inhibits extracellular MET activation.
  • Exploration of MET inhibitors in combination with other lung cancer therapies.

Main Results:

  • Small molecule MET inhibitors reviewed include tivantinib, cabozantinib, crizotinib, amuvatinib, MGCD265, foretinib, MK2461, SGX523, PHA665752, JNJ-38877605, SU11274, and K252A.
  • Onartuzumab (MetMAb) prevents MET receptor activation by HGF.
  • MET inhibition demonstrates potential to counteract the negative prognostic impact of MET expression and overcome acquired resistance to EGFR inhibitors.

Conclusions:

  • MET inhibitors offer a therapeutic strategy for NSCLC, addressing both tumor progression and resistance mechanisms.
  • Combination therapies involving MET inhibitors may enhance treatment efficacy in lung cancer.
Keywords:
METNon-small cell lung cancertargeted therapiestyrosine kinase inhibitors

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