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

• Published in: Prostate cancer and prostatic diseases 2016-09, Vol.19 (3), p.231-241
• Main Authors: Antonarakis, E S, Armstrong, A J, Dehm, S M, Luo, J
• Format: Article
• Language: English
• Subjects: 631/67/1059; 692/699/67; Alternative Splicing; Androgen Receptor Antagonists - therapeutic use; Androgen receptors; Androgens; Androgens - metabolism; Animals; Antineoplastic Agents, Hormonal - therapeutic use; Biomarkers; Biomarkers, Tumor; Biomedical and Life Sciences; Biomedicine; Cancer Research; Castration; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Clinical trials; Clinical Trials as Topic; Deoxyribonucleic acid; DNA; Domains; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm - drug effects; Epithelium - metabolism; Epithelium - pathology; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic Variation; Heterogeneity; Humans; Isoforms; Male; Metastases; Molecular Targeted Therapy; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Binding; Protein Interaction Domains and Motifs; Protein Multimerization; Receptors; Receptors, Androgen - chemistry; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; review; Signal Transduction - drug effects; Therapeutic targets; Transcription, Genetic; Treatment Outcome; Tumor cells; Tumors
• ISSN: 1365-7852; 1476-5608
• DOI: 10.1038/pcan.2016.17

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 NH 2 -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.