Abstract 5116: Inhibition of PI3K/AKT signaling by NVP-BKM120 promotes ABT-737-induced toxicity in established and primary cultured glioblastoma cells

Abstract

Abstract Identification of therapeutic strategies that might enhance the efficacy of Bcl-2 inhibitor ABT-737 is of great interest in many cancers including glioma. Our recent study suggested that Akt is a crucial mediator of apoptosis sensitivity in response to ABT-737 in glioma cell lines. Inhibitors of PI3-K/Akt are currently being assessed clinically in patients with glioma, as PI3K/Akt inhibition would be expected to have many pro-apoptotic effects, we hypothesized that there may be unique synergy between PI3-K inhibitors and BH3-mimetics. We assessed the combination of the PI3K inhibitor BKM120 and the Bcl-2 family inhibitor ABT-737 in established and primary cultured glioma cells. We found that the combined treatment with these agents led to a significant activation of caspase-8, 3, PARP and cell death irrespective of PTEN status. The enhanced lethality observed with the combination also appears dependent upon the loss of mitochondrial membrane potential, release of cytochrome c, smac/DIABLO and apoptosis-inducing factor to the cytosol. Further study revealed that the upregulation of Noxa, truncation of Bid, activation of Bax and Bak caused by these inhibitors was the key factor for the synergy. In addition, we demonstrated the release of proapoptotic proteins Bim and Bak from Mcl-1. We found defects in chromosome segregation leading to multinuclear cells and loss of colony forming ability, suggesting the potential use of BKM120 as a promising agent to improve the anti-cancer activities of ABT-737. Citation Format: Esther P. Jane, Daniel R. Premkumar, Alejandro Morales, Kimberly A. Foster, Ian Pollack. Inhibition of PI3K/AKT signaling by NVP-BKM120 promotes ABT-737-induced toxicity in established and primary cultured glioblastoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5116. doi:10.1158/1538-7445.AM2014-5116