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Synergistic effects of foretinib with HER-targeted agents in MET and HER1- or HER2-coactivated tumor cells

Li Liu1, Hong Shi, Yuan Liu

  • 1GlaxoSmithKline, 17.1356I, 5 Moore Drive, Research Triangle Park, NC 27709-3398, USA.

Molecular Cancer Therapeutics
|January 22, 2011
PubMed

Insights

Combination therapy targeting both MET and HER pathways shows promise for certain cancers. MET inhibitors like foretinib combined with HER-targeted drugs (erlotinib, lapatinib) demonstrate effectiveness in preclinical models and suggest clinical utility.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Coactivation of MET and Human Epidermal growth factor Receptor (HER) tyrosine kinases occurs in various human tumors.
  • MET activation can interfere with the efficacy of HER-targeted therapies.

Purpose of the Study:

  • To investigate MET and HER expression and signaling in human tumor cell lines.
  • To evaluate the efficacy of foretinib, a MET inhibitor, alone and in combination with HER-targeted agents (erlotinib, lapatinib).
  • To explore the role of MET activation in resistance to HER-targeted therapies.

Main Methods:

  • Characterization of MET and HER expression and signaling in tumor cell lines.
  • Assessment of cell line sensitivity to foretinib, erlotinib, and lapatinib, as single agents and in combination.
  • Western blot analysis to assess signaling pathway phosphorylation.
  • Retrospective analysis of MET expression in HER2-positive breast cancer patients treated with lapatinib.

Main Results:

  • MET-amplified tumor lines without HER amplification were sensitive to foretinib.
  • MET-amplified lines with HER1 or HER2 amplification showed greater sensitivity to combination therapy.
  • Hepatocyte growth factor (HGF)-induced resistance to lapatinib/erlotinib was reversed by MET inhibition.
  • Combination therapy effectively reduced phosphorylation of MET, HER, AKT, and ERK.
  • Higher tumor MET expression in HER2-positive breast cancer patients correlated with shorter progression-free survival on lapatinib therapy.

Conclusions:

  • Combination therapy with foretinib and HER-targeted agents is a potential treatment strategy for tumors with MET amplification or overexpression and HER1/HER2 coactivation.
  • MET signaling plays a crucial role in mediating resistance to HER-targeted therapies.
  • Targeting both MET and HER pathways may overcome resistance and improve treatment outcomes in specific cancer patient populations.

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