Preclinical Evaluation of MET Inhibitor INC-280 With or Without the Epidermal Growth Factor Receptor Inhibitor Erlotinib in Non-Small-Cell Lung Cancer

Matthew S. Lara, William S. Holland, Danielle Chinn, Rebekah A. Burich, Primo N Lara, David R Gandara, Karen Kelly, Philip Mack

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Background: Although the epidermal growth factor receptor (EGFR) inhibitor erlotinib is initially effective in non-small-cell lung cancer (NSCLC) patients with tumors harboring activating mutations of . EGFR, most subsequently develop acquired resistance. One recognized resistance mechanism occurs through activation of bypass signaling via the hepatocyte growth factor (HGF)-MET pathway. INC-280 is a small molecule kinase inhibitor of MET. We sought to demonstrate the activity of INC-280 on select NSCLC cell lines both as a single agent and in combination with erlotinib using exogenous HGF to simulate MET up-regulation. Methods: Four NSCLC cell lines (HCC827, PC9, H1666, and H358) were treated with either single-agent INC-280 or in combination with erlotinib with or without HGF. The activity of the drug treatments was measured by cell viability assays. Immunoblotting was used to monitor expression of EGFR/pEGFR, MET/pMET, GAB1/pGAB1, AKT/pAKT, and ERK/pERK as well as markers of apoptosis (PARP and capase-3 cleavage) in H1666, HCC827, and PC9. Results: As a single agent, INC-280 showed minimal cytotoxicity despite potent inhibition of MET kinase activity at concentrations as low as 10 nM. Addition of HGF prevented erlotinib-induced cell death. The addition of INC280 to HGF-mediated erlotinib-resistant models restored erlotinib sensitivity for all cell lines tested, associated with cleavage of both PARP and caspase-3. In these models, INC-280 treatment was sufficient to restore erlotinib-induced inhibition of MET, . GAB1, . AKT, and . ERK in the presence of HGF. Conclusion: Although the MET inhibitor INC-280 alone had no discernible effect on cell growth, it was able to restore sensitivity to erlotinib and promote apoptosis in NSCLC models rendered erlotinib resistant by HGF. These data provide a preclinical rationale for an ongoing phase 1 clinical trial of erlotinib plus INC-280 in . EGFR-mutated NSCLC.

Original languageEnglish (US)
JournalClinical Lung Cancer
StateAccepted/In press - Mar 22 2016


  • Acquired resistance
  • AKT
  • Combination therapy
  • EGFR mutant
  • ERK

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research


Dive into the research topics of 'Preclinical Evaluation of MET Inhibitor INC-280 With or Without the Epidermal Growth Factor Receptor Inhibitor Erlotinib in Non-Small-Cell Lung Cancer'. Together they form a unique fingerprint.

Cite this