Abstract 72: Targeting PI-3K/Akt signaling pathway by a PI-3K inhibitor BKM120 for radiosensitization in murine hepatocellular carcinoma.

Abstract

Abstract Purpose: Tumor control of hepatocellular carcinoma (HCC) by radiotherapy remains unsatisfactory and the sub-lethal effect associates with secondary spread. Phosphatidylinositol 3-kinase (PI-3K)/Akt pathway plays a critical role in promoting cancer cell proliferation and inhibiting cell death. Elevated PI-3K/Akt activity is associated with increased cellular resistance to irradiation. Our aim was to assess if the inhibition of PI-3K/Akt activity by a PI-3K inhibitor, BKM120, contributes to the increasing sensitivity of murine liver cancer cells to irradiation. Methods and Materials: Murine HCC cell line (BNL) was used to evaluate the in vitro synergism of combining BKM120 with irradiation. Flow cytometry analyzed the cell cycle changes, whereas Western blot investigated the protein expressions after the combined treatment. Balb/c mice bearing ectopic BNL xenografts were treated with BKM120 and/or radiotherapy for the in vivo response. Results: Clonogenic cell survival decreased dose-dependently either with irradiation or BKM120 treatment. Synergisms were achieved in cells treated together with greater or equal than 0.5μM BKM120 and 2 Gy radiation. BKM120 pretreatment significantly inhibited radiation-induced Akt phosphorylation. Western blots of active caspase-3 and cleaved PARP revealed that the combined BKM120 and radiation treatment strongly increased the expression of these apoptotic markers in response to irradiation compared with radiation alone. In ectopic xenografts, pretreatment with BKM120 significantly enhanced the tumor-suppressive effect by radiotherapy. Conclusion: The apparent synergism between BKM120 and irradiation or effect of pre-treatment with BKM120 suggests an option to mitigate the activation of Akt by radiation, leading to increased cell apoptosis in murine liver cancer. These data suggest that the BKM120/radiation combination be a strategy worthy of further clinical trials. Citation Format: Wei-Lin Liu, Melissa Gao, Ann-Lii Cheng, Jason Chia-Hsien Cheng. Targeting PI-3K/Akt signaling pathway by a PI-3K inhibitor BKM120 for radiosensitization in murine hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 72. doi:10.1158/1538-7445.AM2013-72