Androgen receptor (AR) aberrations in castration-resistant prostate cancer.

Genetic aberrations affecting the androgen receptor (AR) are rare in untreated prostate cancers (PCs) but have been found in castration-resistant prostate cancers (CRPCs). Further, successful treatment with novel endocrine therapies indicates that CRPCs remain androgen-sensitive. Known AR aberrations include amplification of the AR gene leading to the overexpression of the receptor, point mutations of AR resulting in promiscuous ligand usage, and constitutively active AR splice variants. Gain, or amplification, of the AR gene is one of the most frequent genetic alterations observed in CRPCs. Up to 80% of CRPCs have been reported to carry an elevated AR gene copy number, and about 30% have a high-level amplification of the gene. AR mutations are also commonly observed and have been found in approximately 10-30% of the CRPC treated with antiandrogens; however, the frequency and significance of AR splice variants is still unclear. Because AR aberrations are found almost exclusively in CRPC, these alterations must have been selected for during therapy. Interestingly, these aberrations lead to activation of the receptor, despite treatment-induced emergence of therapy-resistant tumor clones. Therefore, future novel treatment strategies should focus on suppressing AR activity in CRPC.