The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Is a Potent Inhibitor of ATM- and DNA-PKCs-Mediated DNA Damage Responses

Abstract

Inhibitors of PI3K/Akt signaling are being actively developed for tumor therapy owing to the frequent mutational activation of the PI3K-Akt-mTORC1 pathway in many cancers, including glioblastomas (GBMs). NVP-BEZ235 is a novel and potent dual PI3K/mTOR inhibitor that is currently in phase 1/2 clinical trials for advanced solid tumors. Here, we show that NVP-BEZ235 also potently inhibits ATM and DNA-PKcs, the two major kinases responding to ionizing radiation (IR)-induced DNA double-strand breaks (DSBs). Consequently, NVP-BEZ235 blocks both nonhomologous end joining and homologous recombination DNA repair pathways resulting in significant attenuation of DSB repair. In addition, phosphorylation of ATMtargets and implementation of the G(2)/M cell cycle checkpoint are also attenuated by this drug. As a result, NVP-BEZ235 confers an extreme degree of radiosensitization and impairs DSB repair in a panel of GBM cell lines irrespective of their Akt activation status. NVP-BEZ235 also significantly impairs DSB repair in a mouse tumor model thereby validating the efficacy of this drug as a DNA repair inhibitor in vivo. Our results, showing that NVP-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 utility of NVP-BEZ235 as an effective radiosensitizer for GBMs in the clinic.

The Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances the Antitumoral Activity of Gemcitabine in Human Pancreatic Cancer Cell Lines

“…They could demonstrate that the mTOR inhibitor rapamycin suppresses DNA double strand break repair. Consistent with this, as shown in Figure 7, sequential application of gemcitabine and NVP-BEZ235 resulted in a significant increase of double-strand breaks analysed with γH2AX assay [36].…”

“…This might be an explanation, why the sequence BEZ235GEM is inferior to the sequence GEMBEZ235 [36].…”

Phosphoproteomic characterization of DNA damage response in melanoma cells following MEK/PI3K dual inhibition

“…Early strategies for targeting PI3K coinhibited the activities of ATM and PRKDC (31,32). PI3K-mTOR dual inhibitors (e.g., NVP-BEZ235, PI-103) also reportedly inhibit ATM and PRKDC in biochemical and cell-culture models (33,34). Used here, GDC-0941 is a pan-class I PI3K inhibitor with enzyme IC 50 values of 0.003 μM (p110α), 0.033 μM (p110β), 0.003 μM (p110δ), or 0.075 μM (p110γ), making it >400 times more selective for p110α/δ than PRKDC (16).…”

Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck

“…BEZ235 (dual PI3K/mTOR inhibitor; Novartis Pharmaceuticals Corporation, East Hanover) is one such inhibitor that has been shown to radiosensitize head and neck carcinoma cells [44,71,72] by interfering with both homologous and nonhomologous recombination DNA repair pathways [73]. Thus, BEZ235 may add potential benefit for patients undergoing RT.…”