Dual PI3K/mTOR Inhibitor NVP-BEZ235 Enhances Radiosensitivity of Head and Neck Squamous Cell Carcinoma (HNSCC) Cell Lines Due to Suppressed Double-Strand Break (DSB) Repair by Non-Homologous End Joining

Abstract

The PI3K/Akt/mTOR pathway is frequently altered in human papillomavirus (HPV)-positive and negative squamous cell carcinoma of the head and neck (HNSCC) and overstimulation is associated with poor prognosis. PI3K drives Akt activation and constitutive signaling acts pro-proliferative, supports cell survival, DNA repair, and contributes to radioresistance. Since the small molecule NVP-BEZ235 (BEZ235) is a potent dual inhibitor of this pathway, we were interested whether BEZ235 could be an efficient radiosensitizer. The 50 nM BEZ235 was found to abrogate endogenous and irradiation-induced phosphorylation of Akt (Ser473). The anti-proliferative capacity of the drug resulted in an increase in G1-phase cells. Repair of radiation-induced DNA double-strand breaks (DSBs) was strongly suppressed. Reduction in DSB repair was only apparent in G1- but not in G2-phase cells, suggesting that BEZ235 primarily affects non-homologous end joining. This finding was confirmed using a DSB repair reporter gene assay and could be attributed to an impaired phosphorylation of DNA-PKcs (S2056). Cellular radiosensitivity increased strongly after BEZ235 addition in all HNSCC cell lines used, especially when irradiated in the G0 or G1 phase. Our data indicate that targeting the PI3K/Akt/mTOR pathway by BEZ235 with concurrent radiotherapy may be considered an effective strategy for the treatment of HNSCC, regardless of the HPV and Akt status.

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

“…Therefore, dual PI3K/AKT/mTOR inhibitors, such as BEZ235 and gdc-0980, are attracting increasing attention from researchers. BEZ235 is the first dual PI3K/mTOR inhibitor to enter clinical trials, the results of which show that the drug is well tolerated and has strong antitumour activity and is thus of substantial value for tumour treatment [81]. Studies on the PI3K/AKT signalling pathway as a targeted cancer therapy have been performed for more than a decade, and the Federal Drug Administration (FDA) has approved p110delta inhibitors for the treatment of certain types of lymphoma, providing hope for cancer treatment.…”

ROS-Mediated Therapeutic Strategy in Chemo-/Radiotherapy of Head and Neck Cancer

“…Irradiation exposure can induce mitochondrial-dependent ROS generation [57]. ROS-modulated DNA damage repair [58][59][60][61], cell death regulation [62][63][64][65], tumor microenvironment [66,67], and CSC characteristics [67,68] greatly affect the radiotherapy efficiency. Among these biological factors, cell death and DNA damage are the most common aspects regulated by cellular redox status.…”

Improving the Efficacy of Tumor Radiosensitization Through Combined Molecular Targeting

“…Schötz et al observed radiosensitization in HNSCC cell lines, regardless of HPV-status. A DNA-repair defect was more apparent in the G1 than G2 phase and reporter gene assays pointed toward inhibition of non-homologous endjoining (NHEJ), but not homologous recombination (HR) ( 70 ). Chang et al also tested an alternative dual PI3K/mTOR inhibitor, PI-103, which caused radiosensitization comparable to dactolisib.…”