New Opportunities for Targeting the Androgen Receptor in Prostate Cancer

Abstract

Recent genomic analyses of metastatic prostate cancer have provided important insight into adaptive changes in androgen receptor (AR) signaling that underpin resistance to androgen deprivation therapies. Novel strategies are required to circumvent these AR-mediated resistance mechanisms and thereby improve prostate cancer survival. In this review, we present a summary of AR structure and function and discuss mechanisms of AR-mediated therapy resistance that represent important areas of focus for the development of new therapies.

Figure 1.

Chromosome, gene, and protein organization of the androgen receptor (AR) and AR variants. (A) The human AR is encoded by a single gene located at Xq11-12 and is normally organized into eight exons, encoding a protein of ∼919 amino acids. The full-length AR protein is divided into structural and functional domains: a large amino-terminal transactivation domain (NTD) containing activation function-1 (AF-1) and -5 (AF-5) and two LxxLL-like motifs ²³FQNLF²⁷ and ⁴³³WHTLF⁴³⁷, a DNA-binding domain (DBD), a small hinge region (H) containing a nuclear localization signal (NLS), and a ligand-binding domain (LBD) containing activation function 2 (AF-2). Gain-of-function mutations in the AR gene as a result of therapy-mediated selection pressure colocate to the LBD. Alternative splicing of cryptic exons (CEs) or exon skipping can give rise to carboxy-terminally truncated AR isoforms. (B) Structure of two clinically relevant AR-Vs, AR-V7 and ARv567es.

Figure 2.

The complex androgen receptor (AR) coregulatory network. A list of experimentally verified AR interacting proteins was obtained from HitPredict (Lopez et al. 2015). Cellular localization of proteins was based on Gene Ontology designations. Proteins were color-coded according to HitPredict interaction scores.