title: Strengthening context-dependent anticancer effects on non-small cell lung carcinoma by inhibition of both MET and EGFR.
abstract: The MET and EGFR receptor tyrosine kinases (RTK) are often coexpressed and may cross-talk in driving the development and progression of non-small cell lung carcinoma (NSCLC). In addition, MET amplification is an alternative resistance mechanism for escaping EGFR-targeted therapy. To assess the benefits of combined targeting of MET and EGFR for treating NSCLCs, we investigated the activities of these two RTK pathways in NSCLC cell lines and evaluated their responses to SGX523 and erlotinib, the small-molecule kinase inhibitors of MET and EGFR, respectively. We showed that MET interacts with and cross-activates EGFR in MET-amplified or -overexpressed cells. The inhibition of both MET and EGFR results in maximal suppression of downstream signaling and of cell proliferation when their ligands are present. Furthermore, we showed that SGX523 plus erlotinib strengthens anticancer activity in vivo in a cellular context-dependent manner. The combination led to the regression of H1993 tumors by enhancing the suppression of proliferation and inducing apoptosis, whereas H1373 tumor growth was significantly reduced by the combination via suppression of proliferation without inducing apoptosis. SGX523 alone was sufficient to achieve near-complete regression of EBC-1 tumors; its combination with erlotinib strongly inhibited the viability of a population of insensitive cells emerging from an SGX523-treated EBC-1 tumor recurrence. Our data suggest that inhibition of both MET and EGFR can enhance anticancer effects against NSCLCs in a context-dependent manner and thus provide a strong rationale for combining MET and EGFR inhibitors in treating NSCLCs.
authors.affiliation: Van Andel Research Institute, Grand Rapids, MI 49503, USA. YuWen.Zhang@vai.org
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Zhang
authors.forename: Ben
authors.initials: B
authors.lastname: Staal
authors.forename: Curt
authors.initials: C
authors.lastname: Essenburg
authors.forename: Steven
authors.initials: S
authors.lastname: Lewis
authors.forename: Dafna
authors.initials: D
authors.lastname: Kaufman
authors.forename: George F
authors.initials: GF
authors.lastname: Vande Woude
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C547925:6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011799:Quinazolines; D014230:Triazoles; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met