The interconnection between androgen receptor and DNA damage response pathways in prostate cancer

The androgen receptor (AR) plays a critical role in the development and progression of prostate cancer by regulating key cellular processes such as cell proliferation and apoptosis. Although traditional AR-targeted therapies have shown initial success, acquired resistance remains a significant clinical challenge, often driven by AR alterations and somatic gene mutations associated with homologous recombination deficiency (HRD). Approximately 20% of advanced prostate cancer cases exhibit HRD, resulting in substantial genomic instability and complicating treatment. Fortunately, Food and Drug Administration-approved poly(ADP-ribose) polymerase inhibitors, including olaparib and rucaparib, exploit synthetic lethality to target prostate cancer with HRD, and additional drugs targeting DNA damage response (DDR) proteins are under development. Emerging evidence suggests that AR activity enhances DDR gene expression, with multiple DDR proteins localized near androgen-regulated regions, highlighting a close interaction between AR and DDR pathways. Consequently, recent preclinical and clinical studies have investigated combining AR-targeted therapies with treatments that induce DNA damage, such as radiation therapy, or inhibit DNA repair mechanisms. This review discusses AR's role in cellular processes, the interplay between AR and DDR, and recent advances in prostate cancer treatment strategies.