Journal Article

Androgen receptor splice variant-7 expression emerges with castration resistance in prostate cancer

Figueiredo, Ines, Sprenger, Cynthia, True, Lawrence D., Dolling, David, Seed, George, Neeb, Antje, Sharp, Adam, Riisnaes, Ruth, Carreira, Suzanne, Luo, Jun, Nelson, Peter S., Rodrigues, Daniel Nava, Uo, Takuma, Plymate, Stephen R., Balk, Steven P., Bertan, Claudia, Morrissey, Colm, Coleman, Ilsa, Welti, Jonathan, de Bono, Johann S., Yuan, Wei, Russo, Joshua W.

2019

Overview

Liquid biopsies have demonstrated that the constitutively active androgen receptor splice variant-7 (AR-V7) associates with reduced response and overall survival from endocrine therapies in castration-resistant prostate cancer (CRPC). However, these studies provide little information pertaining to AR-V7 expression in prostate cancer (PC) tissue. Following generation and validation of a potentially novel AR-V7 antibody for IHC, AR-V7 protein expression was determined for 358 primary prostate samples and 293 metastatic biopsies. Associations with disease progression, full-length androgen receptor (AR-FL) expression, response to therapy, and gene expression were determined. We demonstrated that AR-V7 protein is rarely expressed (<1%) in primary PC but is frequently detected (75% of cases) following androgen deprivation therapy, with further significant (P = 0.020) increase in expression following abiraterone acetate or enzalutamide therapy. In CRPC, AR-V7 expression is predominantly (94% of cases) nuclear and correlates with AR-FL expression (P ≤ 0.001) and AR copy number (P = 0.026). However, dissociation of expression was observed, suggesting that mRNA splicing remains crucial for AR-V7 generation. AR-V7 expression was heterogeneous between different metastases from a patient, although AR-V7 expression was similar within a metastasis. Moreover, AR-V7 expression correlated with a unique 59-gene signature in CRPC, including HOXB13, a critical coregulator of AR-V7 function. Finally, AR-V7-negative disease associated with better prostate-specific antigen (PSA) responses (100% vs. 54%, P = 0.03) and overall survival (74.3 vs. 25.2 months, hazard ratio 0.23 [0.07-0.79], P = 0.02) from endocrine therapies (pre-chemotherapy). This study provides impetus to develop therapies that abrogate AR-V7 signaling to improve our understanding of AR-V7 biology and to confirm the clinical significance of AR-V7. Work at the University of Washington and in the Plymate and Nelson laboratories is supported by the Department of Defense Prostate Cancer Research Program (W81XWH-14-2-0183, W81XWH-12-PCRP-TIA, W81XWH-15-1-0430, and W81XWH-13-2-0070), the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the Institute for Prostate Cancer Research, the Veterans Affairs Research Program, the NIH/National Cancer Institute (P01CA163227), and the Prostate Cancer Foundation. Work in the de Bono laboratory was supported by funding from the Movember Foundation/Prostate Cancer UK (CEO13-2-002), the US Department of Defense (W81XWH-13-2-0093), the Prostate Cancer Foundation (20131017 and 20131017-1), Stand Up To Cancer (SU2C-AACR-DT0712), Cancer Research UK (CRM108X-A25144), and the UK Department of Health through an Experimental Cancer Medicine Centre grant (ECMC-CRM064X).

• Publisher: American Society for Clinical Investigation
• Subject: Acetic acid / Alternative Splicing / Androgen receptors / Androgens / Animals / Antineoplastic Agents, Immunological - pharmacology / Biology / Biomedical research / Cancer patients / Cancer therapies / Castration / Cell cycle / Cell Line, Tumor / Chemotherapy / Clinical Medicine / Copy number / Development and progression / Diagnosis / Endocrine therapy / Gene expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Health aspects / Humans / Laboratories / Ligands / Male / Medical research / Metastases / Metastasis / Mice / Mice, Inbred ICR / Mice, SCID / Neoplasm Metastasis / Neoplasm Proteins - biosynthesis / Neoplasm Proteins - genetics / Patients / Prostate cancer / Prostate-specific antigen / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - genetics / Prostatic Neoplasms, Castration-Resistant - metabolism / Prostatic Neoplasms, Castration-Resistant - pathology / Protein expression / Proteins / Receptors, Androgen - biosynthesis / Receptors, Androgen - genetics / Splicing / Studies / Survival / Xenograft Model Antitumor Assays