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
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