Radiation Biology

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SU_43_2430 - A Selective Small Molecule Inhibitor of c-Met Kinase, BPI-9016M, has Synergistic Effects with Radiation on Esophageal Squamous Cell Carcinoma

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

A Selective Small Molecule Inhibitor of c-Met Kinase, BPI-9016M, has Synergistic Effects with Radiation on Esophageal Squamous Cell Carcinoma
C. Jiang1, S. Han2, G. Lin2, F. Gu2, Q. Lin2, J. Feng3, and Y. Xu1; 1Department of Radiation Oncology, Shanghai Pulmonary Hospital, Shanghai, China, 2Zhejiang Cancer Hospital, Hangzhou, China, 3Zhejiang Cancer Research Institution, Hangzhou, China

Purpose/Objective(s): Hepatocyte growth factor receptor (c-Met) is overexpressed in cancer and plays a crucial role in inhibition of apoptosis. The small-molecule c-Met inhibitor BPI-9016M can enhance the cytotoxicity of various DNA-damaging agents and promote apoptosis. Here, we evaluated the radiosensitizing potential of BPI-9016M in Eca109 human esophageal squamous cell carcinoma (ESCC) cells.

Materials/Methods: Cell viability was determined using the CCK-8 assay. The radiosensitizing effect of BPI-9016M was evaluated using the clonogenic survival assay and a murine tumor xenograft model. Apoptosis was determined by flow cytometric analysis and TUNEL staining. Apoptosis-related proteins were detected by western blot analysis. Radiation-induced DNA double strand break and homologous recombination repair were probed by assessing activation of the ATR-Chk1/ATM-Chk2 pathways.

Results: BPI-9016M induced a radiosensitizing effect in Eca109 cells and reduced clonogenic survival in vitro. Combination of BPI-9016M with irradiation delayed the growth of ESCC tumor xenografts more significantly that either treatment alone (P < 0.05). The radiosensitizing effects of BPI-9016M were due to increased apoptosis, as confirmed by upregulation of cleaved-caspase 3 and 9, downregulation of mutant P53 and Bcl-2, decreased phosphorylation of ATR and ATM, and inhibition of γ-H2AX accumulation both in vitro and in vivo.

Conclusion: These findings suggest BPI-9016M exerts a radiosensitizing effect to enhance apoptosis by inhibiting homologous recombination DNA repair in irradiated ESCC cells.

Author Disclosure: C. Jiang: None. S. Han: None. F. Gu: None. J. Feng: None.

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SU_43_2430 - A Selective Small Molecule Inhibitor of c-Met Kinase, BPI-9016M, has Synergistic Effects with Radiation on Esophageal Squamous Cell Carcinoma



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