Androgen Receptor Signaling in Castration Resistant Prostate Cancer

Prostate cancer (PCa) is the second most frequently diagnosed cancer in men in the United States. Following androgen deprivation therapy, advanced PCa usually evolves into a refractory stage termed castration resistant prostate cancer (CRPC), which is responsible for most mortality. Importantly, androgen receptor (AR) signaling is still active in CRPC. Therefore, next-generation drugs that inhibit AR signaling such as enzalutamide and abiraterone are used for therapy for many patients with CRPC. These drugs provide a survival benefit but are not curative. In this article, we review the mechanisms through which the AR signaling axis promotes resistance to androgen-deprivation therapy and drives progression of CRPC. There are a number of pathways that allow AR to escape androgen-deprivation therapy, including activation of glucocorticoid receptors, synthesis of androgens in CRPC tissues, AR mutations, AR amplification and AR splice variants. Although the AR appears to be involved in resistance to other therapeutics such as the taxanes, which disrupt normal microtubule function, this article will focus on the role of AR in resistance to androgen-deprivation therapy.