Androgen receptor variants mediate DNA repair after prostate cancer irradiation

In prostate cancer (PCa), androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. Since a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARV increase the clonogenic survival of PCa cells after irradiation in an ADT-independent manner. Notably, PCa cell irradiation trigger binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacological inhibition of DNA-PKc blocked this interaction, increased DNA damage and elevated PCa cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized PCa.

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