P3.17-003 A Selective Small Molecule Inhibitor of C-Met Kinase, BPI-9016M, Has Synergistic Effects with Radiation on Esophageal Squamous Cell Carcinoma

Abstract

c-Met is overexpressed in cancer cells and plays a crucial role in apoptosis evasion. BPI-9016M, a small-molecule inhibitor of c-Met, could enhance the cytotoxicity of various DNA-damaging agents and promote the cell apoptosis. Here, we evaluated the radiosensitizaion potential of BPI-9016M in Eca109 human esophageal squamous cell carcinoma (ESCC) cell line. Cell viability was determined by CCK8 assay. The radiosensitization effect of BPI-9016M was evaluated by clonogenic survival and progression of tumor xenograft. Cell apoptosis were determined by flow cytometric analysis and TUNAL. Cell apoptosis regulators were detected by western blot analysis. Radiation-induced DNA double strand break (DSB) and homologous recombination repair (HRR) were detected by the activation of ATR-Chk 1/ATM-Chk2 pathways. BPI-9016M induced radiosensitization in Eca109 cell of ESCC cell line, associated with 1) down-regulating mutation P53 and Bcl-2; 2) decreases phosphorylated ATR and ATM focus formation, and the expression of γ-H2AX; 3) up-regulates the rate of cell apoptosis protein cleaved-Caspase(Figure 1). The combination of BPI-9016M with irradiation delayed the growth of ESCC tumor xenograft to a greater extent compared with either treatment modality alone (P < 0.05). Figure 1. BPI-9016M enhanced radiation induced apoptosis and inhibited ATM- and ATR-dependent DNA damage homologous recombination repair (HRR) pathways analyzed by western blot. Our findings suggest that the enhanced apoptosis and the inhibition of HRR contribute to radiosensitization by c-Met inhibitor BPI-9016M in ESCC cell.