Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting

Abstract

While there are myriad mechanisms of primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer, the potential role of androgen receptor splice variants (AR-Vs) has recently gained momentum. AR-Vs are abnormally truncated isoforms of the androgen receptor (AR) protein that lack the COOH-terminal domain but retain the NH2-terminal domain and DNA-binding domain and are thus constitutively active even in the absence of ligands. Although multiple preclinical studies have previously implicated AR-Vs in the development of castration resistance as well as resistance to abiraterone and enzalutamide, recent technological advances have made it possible to reliably detect and quantify AR-Vs from human clinical tumor specimens including blood samples. Initial clinical studies have now shown that certain AR-Vs, in particular AR-V7, may be associated with resistance to abiraterone and enzalutamide but not taxane chemotherapies when detected in circulating tumor cells. Efforts are now underway to clinically validate AR-V7 as a relevant treatment-selection biomarker in the context of other key genomic aberrations in men with metastatic castration-resistant prostate cancer. Additional efforts are underway to therapeutically target both AR and AR-Vs either directly or indirectly. Whether AR-Vs represent drivers of castration-resistant prostate cancer, or whether they are simply passenger events associated with aggressive disease or clonal heterogeneity, will ultimately be answered only through these types of clinical trials.

Figure 1

Domain structures of full-length androgen receptor and androgen receptor splice variants. Full-length androgen receptor and androgen receptor splice variants share a core structure composed of the transcriptionally active AR NH₂-terminal domain encoded by exon 1 and the DNA-binding domain encoded by exons 2 and 3. Androgen receptor splice variants (AR-Vs) lack the AR ligand-binding domain (LBD), which is the binding site for agonists testosterone (T) and DHT and competitive antagonists such as enzalutamide. Instead of a ligand-binding domain, androgen receptor splice variants contain CTE of variable length and sequence, which arise from exon skipping or splicing of various CE. Amino-acid sequences of CTEs from selected androgen receptor splice variants are shown. AR, androgen receptor; CE, cryptic exons; CTE, COOH-terminal extensions; DHT, dihydrotestosterone.

Figure 2

Mechanisms of castration-resistant progression, reflecting various molecular disease states. AR, androgen receptor; LBD, ligand-binding domain; mCRPC, metastatic castration-resistant prostate cancer.