Abstract 321: S49076, a novel kinase inhibitor of MET, AXL and FGFR, demonstrates marked in vitro and in vivo efficacy in hepatocellular carcinoma

Abstract

Abstract Introduction: Hepatocellular carcinoma (HCC) is the second cause of cancer-related deaths worldwide. While sorafenib may improve overall survival in advanced HCC, new therapies are needed. Both preclinical and clinical data support a role of MET and AXL receptor tyrosine kinases in HCC progression. We thus evaluated S49076, a novel MET/AXL/FGFR inhibitor in HCC cell lines in vitro and in a transgenic mouse model of HCC. Materials and Methods: MET and AXL expressions were assessed in a panel of HCC cell lines by western blot. Downstream signaling pathways were investigated in the presence of HGF, GAS6 and S49076. Cell invasion was evaluated on matrigel assay. Transgenic mice developing stage-defined HCC were treated with S49076 (50mg/kg). Tumor response was evaluated measuring liver volume by echo-doppler and the number of tumor nodules at intermediary (12weeks) and final sacrifice (16 weeks). Results: Both MET and AXL are expressed in the majority of HCC lines screened. Notably, a high level of AXL was observed in the SK-HEP1 cells which were therefore selected for further investigation. MET and AXL pathways were strongly stimulated by their respective ligands, HGF and GAS6. Combination of HGF and GAS6 led to marked activation of ERK. S49076 inhibited MET and AXL pathway activation and HGF- and GAS6- induced invasion at nanomolar concentrations. In vivo anti-tumor efficacy of S49076 was demonstrated in a transgenic MET-expressing mouse model of HCC. Conclusion: S49076 displayed strong MET and AXL pathway inhibition and anti-invasive properties in SK-HEP1 HCC cells. Moreover, S49076 demonstrated antitumor activity in a mouse model of HCC. Together, these results would support development of S49076 as an innovative treatment in HCC patients. Citation Format: Annemilai Tijeras-Raballand, Adrien Pasteur-Rousseau, Matthieu Martinet, Philippe Bonnin, Marc Pocard, Sébastien Banquet, Valérie Cattan, Eric Raymond, Armand de Gramont. S49076, a novel kinase inhibitor of MET, AXL and FGFR, demonstrates marked in vitro and in vivo efficacy in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 321.