MET is a transmembrane tyrosine kinase receptor that is deregulated (gene amplification, mutation and over-expression) across multiple cancer types. Signaling through MET is normally activated through interactions with its specific ligand, hepatocyte growth factor (HGF). Aberrant MET/HGF activation can stimulate tumor growth, promote angiogenesis, induce metastasis and may contribute to resistance mechanisms in several tumor types. Several non-selective MET inhibitors have entered clinical development; results have been mixed based on potency, selectivity, and/or patient selection. Volitinib is a potent (IC50 4 nM) and selective (>650 fold selectivity over 265 kinases), small molecule inhibitor of MET. Recent evaluation of Volitinib across a panel of cancer cell lines demonstrated selectivity for MET-driven disease, with MET amplified cell lines being most sensitive (IC50s of 1nM) and also suggesting limited off target activity. Volitinib resistant cell lines with MET amplification were identified and used to better understand the relationship of concurrent mutations with response. In addition to cancer cell line selectivity, we are analyzing preclinical models of NSCLC (non small cell lung cancer) that are representative of key patient segments, namely MET amplification and over expression. In newly diagnosed NSCLC adenocarcinomas, focal MET amplification events represent ∼3% of the population while over expression of MET (without gene amplification) is observed in the majority of patients. In preclinical models, focal Met amplification in EBC-1 and NCI-H1993 caused significant tumor growth inhibition, confirming sensitivity to Volitinib. Given the prevalence of over expression in NSCLC, however, we sought to build a platform of evidence for the therapeutic use of Volitinib in preclinical models lacking amplification of the MET gene. Using a patient-derived xenograft model (PDX) of EGFR WT, KRAS WT and metastatic NSCLC disease (HLXF-036LN), we demonstrate that Volitinib induces tumor regression as monotherapy and has added therapeutic benefit when used in combination with taxotere. In addition, we show robust efficacy effects for additional preclinical models, LG0567, LG0645 and Calu-3, for either Volitinib alone or in combination with taxotere. In parallel pharmacodynamic studies, we demonstrate that Volitinib inhibits p-MET and downstream signaling in each model. Together, using an integrated platform of molecular characterization and MET FISH and IHC scores, corresponding antitumor responses to Volitinib are being evaluated for several patient segments. We are using these studies to inform the design of patient selection criteria for upcoming clinical trials in NSCLC.
Citation Format: Celina D'Cruz, Melanie Frigault, Ammar Adam, Minhui Shen, Garry Beran, Evan Barry, Paul Gavine, Yongxin Ren, Shiming Fan, Feng Zhou, Weiguo Qing, Mike Zinda, Weiguo Su, Edwin Clark. Targeting MET in preclinical models to support the clinical development of Volitinib in NSCLC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3114. doi:10.1158/1538-7445.AM2014-3114