In prostate cancer, 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. As 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 ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer 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 prostate cancer.
Bibliographical noteFunding Information:
This work was supported by the following grants: W81XWH-15-1-0128 (to Y. Yin), W81XWH-14-1-0556 (to Y.Yin), W81XWH-13-2-0093 (to G.V. Raj), and W81XWH-12-1-0288 (to G. V. Raj) from the Department of Defense, 1R01CA200787-01 (to G.V. Raj), R01CA174777 (to S.M. Dehm), RO1CA149461, RO1CA197796 and R21CA202403 (to S. Burma), R01CA166677 (to B.P. Chen), UL1TR001105 (to C. Xing), and R00CA160640 (to R. S. Mani) from the NIH, NNX16AD78G from the National Aeronautics and Space Administration (to S. Burma), and the Mimi and John Cole Prostate Cancer Fund (to G.V. Raj).
F.Y. Feng is the founder of PFS Genomics, reports receiving a commercial research grant from Varian, and is a consultant/advisory board member for Dendreon, EMD Serono, Ferring, Janssen, Medivation/Astellas, and Sanofi. J.S. de Bono has received speakers bureau honoraria from AstraZeneca and is a consultant/advisory board member for Astellas, AstraZeneca, Bayer, Genentech/