Abstract 3514: Inhibition of PI-3 kinase signaling potentiates the apoptotic response to mitotic arrest

Abstract

Abstract Anti-mitotic drugs represent a common strategy for cancer chemotherapy by inducing a prolonged prometaphase delay and eventual cell death by apoptosis. Kinesin Spindle Protein (KSP) inhibitors arrest cells in mitosis by blocking bipolar spindle assembly, and these drugs have demonstrated limited side effects in clinical trials. However, they are not as effective as Taxol, whose efficacy is limited by the frequent development of resistance as well as the deleterious effects on non-dividing cells. Recent studies suggest that the ability of cells to maintain energy levels during mitosis could account for the differential responses of cancer cells to mitotic arrest. To determine if manipulating cellular metabolism could potentiate the efficacy of KSP inhibitors, we arrested cells in mitosis in the absence or presence of the PI3-kinase LY294002, and probed for the induction of apoptosis. Because tumor cells respond differently to mitotic arrest, we employed two cell lines that either survive mitotic arrest (MCF7) or undergo apoptosis shortly following mitotic slippage (HeLa). In both cases, simultaneous inhibition of KSP and PI3-kinase induced apoptosis more effectively than mitotic arrest or PI3-K inhibition alone. In the case of HeLa cells, there also appeared to be an acceleration of cell death such that arrested cells underwent apoptosis prior to mitotic slippage. Similar effects were observed using Akt inhibitors, providing additional evidence that PI3-kinase signaling was critical for surviving mitotic arrest. Lastly, we found that increased glucose had a protective effect, further supporting the notion that the ability to survive mitotic arrest depended on the ability to maintain energy levels. If confirmed, this may represent a novel approach for potentiating the anti-tumor activity of KSP inhibitors in the clinic. Citation Format: Roaa M. Kassim, Charles B. Shuster. Inhibition of PI-3 kinase signaling potentiates the apoptotic response to mitotic arrest. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3514.