Androgen Receptor Rearrangement and Splicing Variants in Resistance to Endocrine Therapies in Prostate Cancer

Abstract

In the last few years, the survival of patients with castration-resistant prostate cancer (CRPC) has significantly improved as a result of the development of second-generation androgen deprivation therapies such as abiraterone and second-generation antagonists such as enzalutamide. However, CRPC patients rapidly develop resistance to these drugs, in many cases because of reactivation of the therapeutic target, the androgen receptor (AR) transcription factor. Several mechanisms responsible for AR transcriptional reactivation have been demonstrated, including mutation, amplification, and rearrangement of the AR gene, transcriptional compensation by alternative steroid receptors, and mutation or copy number alteration of genes encoding AR coregulators. In addition, CRPC tumors display elevated expression of truncated AR variants (AR-Vs) that can arise from alternative splicing or underlying AR gene rearrangements. In this review, we discuss general mechanisms of resistance to androgen/AR-targeted therapies, with a focus on the role of AR-Vs in conferring resistance to abiraterone or enzalutamide in CRPC patients.

Figure 1.

A summary of molecular alterations leading to persistent AR signaling that supports castration resistance. In castration-resistant prostate cancer cells, adrenal androgens can be converted to dihydrotestosterone (DHT). DHT binds to AR in the cytoplasm and promotes translocation of AR into the nucleus, where it binds as a dimer to AREs for gene activation or repression. Abiraterone inhibits the androgen steroidogenesis enzyme CYP17A1. Enzalutamide inhibits AR signaling by competing with DHT for binding to the AR LBD. Enzalutamide also inhibits nuclear translocation and binding of AR to AREs. GSR, genomic structural rearrangement.