Alterations in DNA repair promote tumor development, but the impact on tumor progression is poorly understood. Here, discovery of a biochemical circuit linking hormone signaling to DNA repair and therapeutic resistance is reported. Findings demonstrate that androgen receptor (AR) activity is induced by DNA damage, and promotes expression and activation of a gene expression program governing DNA repair. Subsequent investigation revealed that activated AR promotes resolution of double-strand breaks and resistance to DNA damage both in vitro and in vivo. Mechanistically, DNAPKcs was identified as a key target of AR after damage, controlling AR-mediated DNA repair and cell survival after genotoxic insult. Finally, DNAPKcs was shown to potentiate AR function, consistent with a dual role in both DNA repair and transcriptional regulation. Combined, these studies identify the AR-DNAPKcs circuit as a major effector of DNA repair and therapeutic resistance, and establish a new node for therapeutic intervention in advanced disease.

Luminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.