title: Preclinical Evaluation of MET Inhibitor INC-280 With or Without the Epidermal Growth Factor Receptor Inhibitor Erlotinib in Non-Small-Cell Lung Cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Davis, CA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Lara
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Davis, CA.
authors.forename: William S
authors.initials: WS
authors.lastname: Holland
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Davis, CA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Chinn
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Davis, CA.
authors.forename: Rebekah A
authors.initials: RA
authors.lastname: Burich
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Davis, CA.
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Davis, CA.
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Davis, CA.
authors.forename: Karen
authors.initials: K
authors.lastname: Kelly
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Davis, CA. Electronic address: pcmack@ucdavis.edu.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001549:Benzamides; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D014227:Triazines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D007093:Imidazoles; D014227:Triazines; D000069347:Erlotinib Hydrochloride; D011065:Poly(ADP-ribose) Polymerases; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D053148:Caspase 3; C000613976:capmatinib
keywords: AKT; Acquired resistance; Combination therapy; EGFR mutant; ERK