Abstract 1786: Characterization of the inhibitory capacity of EMD1214063, a novel small molecule inhibitor of the MET hepatocyte growth factor receptor on a panel of MET mutated variants

Abstract

Abstract The receptor tyrosine kinase MET is a prime target in clinical oncology because of its aberrant activation in a broad spectrum of malignancies. Here, we tested the anti tumor activity of a novel MET inhibitor, EMD1214063, on cancer cells overexpressing MET and in eight transfected NIH3T3 cell lines expressing different activating mutants of the MET kinase. Our results demonstrate a dose-dependent decrease in MET autophosphorylation in both MET overexpressing cell lines (IC50 of 20nM and 30nM for GTL-16 and H1993, respectively) and in six of the eight cell lines transfected with MET activating mutants (IC50 5-18nM). Blockade of MET by EMD1214063 resulted in reduced downstream activation of AKT, ERK and PLCγ. In contrast, lack of MET inhibition by EMD1214063 in the resistant Y1248H and L1213V MET mutants was associated with high levels of AKT, ERK and PLCγ activation. In all sensitive mutants, EMD1214063 attenuated MET-dependent cellular proliferation and significantly altered cell cycle distribution profiles (increase in G1 and concomitant decrease of S phase). Furthermore, EMD1214063 strongly affected MET-driven biological functions, such as cellular morphology, motility and anchorage-independent growth. To assess the in vivo efficacy of EMD1214063, we established tumor transplantation models exploiting NIH3T3 cells expressing the H1112L or L1213V MET mutants, respectively sensitive and resistant, to in vitro treatment with EMD1214063. Animals bearing H1112L or L1213V tumors were randomized for the treatment with EMD1214063 (50mg/kg/day) or vehicle only. Remarkably, 5 days of treatment with EMD1214063 induced complete regression of sensitive H1112L tumors, while tumor growth remained unaffected in mice injected with resistant L1213V tumor cells and in vehicle-treated mice. Taken together, these results underscore the concordance between in vitro and in vivo effects of EMD1214063 and strongly support its efficacy in inhibiting MET-driven tumor cell growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1786. doi:1538-7445.AM2012-1786