Resistance to second generation antiandrogens in prostate cancer: pathways and mechanisms

Androgen deprivation therapy targeting the androgens/androgen receptor (AR) signaling continues to be the mainstay treatment of advanced-stage prostate cancer. The use of second-generation antiandrogens, such as abiraterone acetate and enzalutamide, has improved the survival of prostate cancer patients; however, a majority of these patients progress to castration-resistant prostate cancer (CRPC). The mechanisms of resistance to antiandrogen treatments are complex, including specific mutations, alternative splicing, and amplification of oncogenic proteins resulting in dysregulation of various signaling pathways. In this review, we focus on the major mechanisms of acquired resistance to second generation antiandrogens, including AR-dependent and AR-independent resistance mechanisms as well as other resistance mechanisms leading to CRPC emergence. Evolving knowledge of resistance mechanisms to AR targeted treatments will lead to additional research on designing more effective therapies for advanced-stage prostate cancer.