DNA-dependent protein kinase (
DNA-PK) plays a pivotal role in the repair of
DNA double-strand breaks (
DSB) and is centrally involved in regulating cellular radiosensitivity. Here, we identify
DNA-PK as a key therapeutic target for augmenting accelerated senescence in irradiated human
cancer cells. We find that
BEZ235, a novel inhibitor of
DNA-PK and
phosphoinositide 3-kinase (PI3K)/mTOR, abrogates radiation-induced
DSB repair resulting in cellular radiosensitization and growth delay of irradiated
tumor xenografts. Importantly, radiation enhancement by
BEZ235 coincides with a prominent p53-dependent accelerated senescence phenotype characterized by positive β-
galactosidase staining, G(2)-M cell-cycle arrest, enlarged and flattened cellular morphology, and increased p21 expression and senescence-associated
cytokine secretion. Because this senescence response to
BEZ235 is accompanied by unrepaired
DNA DSBs, we examined whether selective targeting of
DNA-PK also induces accelerated senescence in irradiated cells. Significantly, we show that specific pharmacologic inhibition of
DNA-PK, but not PI3K or
mTORC1, delays
DSB repair leading to accelerated senescence after radiation. We additionally show that PRKDC knockdown using
siRNA promotes a striking accelerated senescence phenotype in irradiated cells comparable with that of
BEZ235. Thus, in the context of
radiation treatment, our data indicate that inhibition of
DNA-PK is sufficient for the induction of accelerated senescence. These results validate
DNA-PK as an important therapeutic target in irradiated
cancer cells and establish accelerated senescence as a novel mechanism of radiosensitization induced by
DNA-PK blockade.