Abstract 3745: The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKcs-mediated DNA damage responses

Abstract

Abstract Inhibitors of PI3K/Akt signaling are being actively developed for tumor therapy due to the frequent mutational activation of the PI3K-Akt-mTORC1 pathway in many cancers, including glioblastomas (GBMs). NVP-BEZ235 is a novel and potent inhibitor of PI3K/Akt signaling that is currently in phase I/II clinical trials. BEZ235 is reported to specifically inhibit PI3Ks and mTOR with little effect on other kinases. However, we find that BEZ235 also potently inhibits the two major kinases responding to DNA double-strand breaks (DSBs), ATM and DNA-PKcs, both in vitro and in vivo. Consequently, BEZ235 blocks both non-homologous end joining (NHEJ) and homologous recombination (HR) DNA repair pathways, resulting in significant attenuation of DSB repair. Additionally, phosphorylation of ATM targets and implementation of the G2/M cell cycle checkpoint are also attenuated by this drug. The consequence is profound radiosensitization at very low concentrations (100 nM) of BEZ235. This radiosensitizing effect is significantly more potent than that seen with much higher concentrations (10 μm) of inhibitors of DNA-PKcs or ATM that are currently being optimized for clinical testing. Since radiotherapy is the standard of care for GBM, we investigated the potential utility of BEZ235 as a radiosensitizing agent in a panel of GBM lines. We find that BEZ235 treatment confers an extreme degree of radiosensitization and significantly attenuates DSB repair irrespective of Akt activation status in these lines. Finally, we show that BEZ235 also significantly impairs DSB repair in a mouse tumor model thereby validating the efficacy of this drug in vivo. Our results, showing that BEZ235 is a potent and novel inhibitor of ATM and DNA-PKcs, have important implications for the informed and rational design of clinical trials involving this drug and also reveal the potential clinical utility of BEZ235 as an effective radiosensitizer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3745. doi:1538-7445.AM2012-3745