Mechanisms of persistent activation of the androgen receptor in CRPC: recent advances and future perspectives

The emergence of castration resistance has remained the primary obstacle in prostate cancer therapy for several decades. Mechanisms likely to be involved in castration-resistant progression have been studied extensively, but have failed to yield many meaningful and effective targets. The re-activation of the androgen receptor (AR) in castration-resistant prostate cancer (CRPC) is now recognized as the central event in this process, and therapeutic modalities are being devised to combat it. A review of literature was performed to highlight the important factors that play a role in the aberrant activation of the AR in CRPC. Seminal and exciting advances made in the past few years in the discovery of the roles of new intrinsic factors such as intracrine androgens, gene fusions involving the ETS oncogenes, and splice variants of the AR are reviewed. New and emerging hypotheses about the involvement of factors such as cytokines and other signaling pathways are discussed. This review summarizes the most recent advances in the persistent activation of the androgen receptor signaling pathway and provides a perspective about their significance in CRPC progression.