Emerging mutations and functional changes of androgen receptor associated with treatment resistance in prostate cancer

Androgen receptor (AR) signaling is deeply involved in prostate cancer (PCa) development and growth, and castration-resistant prostate cancer (CRPC) transformation. Currently, the use of anti-androgen drugs, such as abiraterone and enzalutamide, has temporary effects on CPRC patients due to several patient-related resistance mechanisms, such as the development of AR mutations. Extensive research is being conducted on AR mutations in both tissues and cell free DNA (cfDNA), in order to identify those mutations responsible for treatment resistance. A recent study identified AR mutations in cfDNA samples from CRPC patients treated with different anti-androgen drugs. In particular, these mutations occurred in exon 8, which codes for ligand binding domain (LBD), causing functional protein changes in vitro, leading to anti-androgen drugs resistance. Moreover, a novel drug tested on PCa cell line, VPC-13566, has been proposed as a potentially alternative therapeutic approach in presence of AR-LBD mutations. This evidence underlines the importance of monitoring AR mutations in cfDNA in order to obtain information about the most efficacious treatment and timely therapy switch.