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Emerging molecular targets in oncology: clinical potential of MET/hepatocyte growth-factor inhibitors

Elizabeth C Smyth1, Francesco Sclafani1, David Cunningham1

  • 1Department of Gastrointestinal Oncology, Royal Marsden Hospital, Sutton, UK.

Oncotargets and Therapy
|June 25, 2014
PubMed

Insights

Dysregulated MET/hepatocyte growth-factor (HGF) signaling drives aggressive cancers. Targeting this pathway with inhibitors shows promise, but clinical trials need patient stratification using validated assays for optimal efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • The MET/hepatocyte growth-factor (HGF) pathway is crucial for normal development and tissue repair.
  • Aberrant MET/HGF signaling, driven by genetic alterations, promotes aggressive cancer phenotypes in various malignancies.
  • MET dysregulation is a significant negative prognostic indicator in cancers like lung, colorectal, gastric, renal, and hepatocellular carcinoma.

Purpose of the Study:

  • To review the role of MET/HGF pathway dysregulation in cancer.
  • To discuss current therapeutic strategies targeting the MET/HGF pathway.
  • To highlight challenges and future directions for MET-targeted therapies, including the need for validated diagnostic assays.

Main Methods:

  • Literature review of studies on MET/HGF signaling in cancer.
  • Analysis of therapeutic approaches, including monoclonal antibodies and small-molecule inhibitors.
  • Examination of resistance mechanisms to MET-targeted therapies.
  • Discussion of clinical trial design considerations.

Main Results:

  • MET/HGF pathway dysregulation contributes to aggressive cancer and poor prognosis.
  • Several MET-targeted therapies, including small-molecule inhibitors and monoclonal antibodies, are in clinical trials.
  • Interactions with other tyrosine kinases like EGFR can lead to therapeutic resistance.
  • Resistance mechanisms include EGFR activation, MET amplification, and gatekeeper mutations.

Conclusions:

  • Targeting the MET/HGF pathway is a promising strategy for various cancers.
  • Overcoming resistance requires understanding complex signaling interactions and developing robust biomarkers.
  • Clinical trials must enroll patients with confirmed MET-pathway dysregulation, necessitating standardized diagnostic assays for effective drug development.
Keywords:
HGFMETNSCLCcabozantinibcolorectal cancergastric cancerhepatocellular canceronartuzumabrenal cancerrilotumumab

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