Androgen Receptor Variant AR-V9 Is Coexpressed with AR-V7 in Prostate Cancer Metastases and Predicts Abiraterone Resistance

Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpos...

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Bibliographic Details
Published in:Clinical cancer research 2017-08, Vol.23 (16), p.4704-4715
Main Authors: Kohli, Manish, Ho, Yeung, Hillman, David W, Van Etten, Jamie L, Henzler, Christine, Yang, Rendong, Sperger, Jamie M, Li, Yingming, Tseng, Elizabeth, Hon, Ting, Clark, Tyson, Tan, Winston, Carlson, Rachel E, Wang, Liguo, Sicotte, Hugues, Thai, Ho, Jimenez, Rafael, Huang, Haojie, Vedell, Peter T, Eckloff, Bruce W, Quevedo, Jorge F, Pitot, Henry C, Costello, Brian A, Jen, Jin, Wieben, Eric D, Silverstein, Kevin A T, Lang, Joshua M, Wang, Liewei, Dehm, Scott M
Format: Article
Language:English
Subjects:
Acetic acid
Androgen receptors
Androgens
Androstenes - therapeutic use
Antisera
Cancer
Castration
Cell Line, Tumor
Cell Proliferation - genetics
Confidence intervals
Disease-Free Survival
Drug Resistance, Neoplasm - genetics
Experimental design
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Gene sequencing
Genetic Variation
Humans
Isoforms
Ligands
Male
Mathematical models
Metastases
Metastasis
Multivariate analysis
Neoplasm Metastasis
Polymerase chain reaction
Prospective Studies
Prostate cancer
Prostatic Neoplasms, Castration-Resistant - drug therapy
Prostatic Neoplasms, Castration-Resistant - genetics
Prostatic Neoplasms, Castration-Resistant - metabolism
Protein Isoforms - genetics
Protein Isoforms - metabolism
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
Ribonucleic acid
RNA
RNA Interference
Tissues
Tumor cells
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Summary:Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 3' terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31-12.2; = 0.02). AR-V9 may be an important component of therapeutic resistance in CRPC. .
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-17-0017