Abstract 4922: The combination of MK-2206 and WZB117 exerts a synergistic cytotoxic effect against breast cancer cells

Abstract

Abstract Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in women. Hormone receptor-positive breast cancer is usually subjected to hormone therapy, while triple-negative breast cancer is more formidable and poses a therapeutic challenge. The PI3K/Akt/mTOR signaling pathway plays a crucial role in cancer cell growth, survival, and metabolism. It has been demonstrated that MK-2206, a potent allosteric Akt inhibitor, is cytotoxic against many cancer cell lines and is currently in clinical development. Cancer cells consume more glucose and rely on glycolysis for energy production even in the presence of abundant oxygen, a phenomenon called the Warburg effect. Therefore, glucose transporters responsible for delivering glucose into cells have become targets for the development of anticancer drugs. In search for anticancer agents whose effect could be enhanced by a GLUT1 inhibitor WZB117, we found that MK-2206, when combined with WZB117, showed a synergistic effect on growth inhibition of breast cancer cells, including ER(+) MCF-7 cells and triple-negative MDA-MB-231 cells. The combination index values at 50% growth inhibition were 0.45 and 0.21, respectively. Western blot analysis of proteins involved in the Akt/mTOR pathway revealed that Akt phosphorylation was markedly suppressed in both cell lines by MK-2206 and WZB117 treatment. Phosphorylation of mTOR and its downstream effectors p70S6K and 4E-BP-1 was also dramatically downregulated in MCF-7 but the effect was not as significant in MDA-MB-231 cells, suggesting that other mechanisms might also contribute to cytotoxicity induced by MK-2206 and WZB117. Further investigation revealed that the combination of MK-2206 and WZB117 induced γ-H2AX, a DNA damage marker, in both cell lines. Results from the comet assay confirmed that MK-2206 and WZB117 induced DNA damage. Protein levels of Rad51 and Ku80, participating in homologous recombination and non-homologous end joining repair respectively, were also decreased in MCF-7 cells, suggesting that MK-2206 and WZB117 may not only cause DNA damage, but also impair DNA repair. Furthermore, MK-2206 or WZB117 alone significantly induced ROS, and the combination of both further increased the ROS level within a short time period. In conclusion, this new finding indicates that MK-2206 and WZB117 may exert a synergistic cytotoxic effect in both ER(+) MCF-7 and triple-negative MDA-MB-231 breast cancer cells via ROS induction, which may in turn cause DNA damage. The combination may also compromise DNA damage repair, and ultimately lead to cell death. This finding may have clinical implications. Citation Format: Yu-Liang Li, Hao-Cheng Weng, Lih-Ching Hsu. The combination of MK-2206 and WZB117 exerts a synergistic cytotoxic effect against breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4922.