Abstract C219: Novel MET/FGFR/AXL kinase inhibitor S49076 exerts radiosensitizing activity in vitro and in vivo.

Abstract

Abstract Background: S49076 was developed as an oral ATP-competitive inhibitor of MET receptor and of other kinases involved in tumor development. It is being assessed as single agent in phase I study. We examined its potential as a radiosensitizer in non-MET dependent tumor models. Experimental Procedures: Cell viability and clonogenic survival assays were performed in two non small-cell lung carcinoma (NSCLC) cells (H460 and A549) and in breast cancer cells MDA-MB-231. Then, the drug was tested in combination with ionizing irradiation (IR) in vitro. The combination was assessed in subcutaneous tumor xenografts and in NSCLC orthotopic models of luciferine-expressing H460luc and A549luc tumors. Immunohistochemical correlates were performed and the activity of S49076 was assessed in a lung metastases model of intravenous injections of A549 cells. Results: The drug as single agent inhibited proliferation (IC50 ranging from 0.50 μM to 1.1 μM) and clonogenic survival (IC50 ranging from 0.34 μM to 0.86 μM). Transcriptomic analyses showed that antitumor effect was associated with modulation of molecular pathways involved in radiation response (p53 and ATM). S49076 and IR inhibited synergistically clonogenic survival in H460 cells: sensitivity enhancement ratio at 0.6 μM was 2 for a single radiation dose of 2 Gy. Combination was additive in A549 and MDA-MB-231 cells. S49076 at 50 mg/kg twice daily enhanced radiation-induced growth delay in subcutaneous tumor xenografts, accompanied with an increase in TUNEL staining. Dose enhancement factors were 3.2 and 1.6 in H460 and A549 tumors, respectively. In lung orthotopic models, S49076 generated significant delay in time course of bioluminescent signal and improved median estimated survival, with significant benefit of combination over either IR or S49076 alone. Finally, treatment with S49076 improved significantly median survival in the lung metastases model (14 versus 22 days, p < 0.001). Conclusions: Altogether, these data suggest that S49076 has a potential as radiosensitizer in non MET-dependent cell lines, and that this effect is accompanied with a modulation of apoptosis. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C219. Citation Format: Cyrus Chargari, Céline Clémenson, Michele Mondini, Charles Ferte, Anne Jacquet-Bescond, Valérie Cattan, Stéphane Depil, Eric Deutsch. Novel MET/FGFR/AXL kinase inhibitor S49076 exerts radiosensitizing activity in vitro and in vivo. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C219.