Targeting extra-gonadal androgens in castration-resistant prostate cancer

•Abiraterone and enzalutamide are effective novel treatments in CRPC.•They target extra-gonadal androgen signaling.•CRPC remains ‘addicted’ to androgen receptor signaling.•Mechanisms of resistance include alternations in the androgen receptor and to steroidogenesis.•Understanding these mechanisms of resistance are important for novel drug discovery.

Metastatic castration resistant prostate cancer (CRPC) is associated with a rise in PSA, suggesting an increase in transcription of steroid receptor regulated genes. The efficacy of the new anti-androgen therapies abiraterone and enzalutamide, that target extra-gonadal activation of androgen signaling, confirm CRPC’s addiction to genes regulated by the androgen receptor (AR). However, patients invariably progress and develop resistance. This review focuses on mechanisms of drug resistance associated with the AR and steroidogenesis in CRPC. Understanding this persistent dependency and adaptation to the androgen axis in CRPC will lead to an understanding of resistance to new licensed therapies and to novel drug discovery, ultimately improving clinical outcome in CRPC.This article is part of a Special Issue entitled ‘Essential role of DHEA’.