September 22, 2019  |  

Androgen receptor variant AR-V9 is co-expressed with AR-V7 in prostate cancer metastases and predicts abiraterone resistance.

Authors: Kohli, Manish and Ho, Yeung and Hillman, David W and Van Etten, Jamie L and Henzler, Christine and Yang, Rendong and Sperger, Jame M and Li, Yingming and Tseng, Elizabeth and Hon, Ting and Clark, Tyson and Tan, Winston and Carlson, Rachel E and Wang, Liguo and Sicotte, Hugues and Thai, Ho and Jimenez, Rafael and Huang, Haojie and Vedell, Peter T and Eckloff, Bruce W and Quevedo, J Fernando and Pitot, Henry C and Costello, Brian and Jen, Jin and Wieben, Eric D and Silverstein, Kevin A T and Lang, Joshua M and Wang, Liewei and Dehm, Scott M

Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies.  Accordingly, efforts are underway 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 co-expressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design:  We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models.  Co-expression 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. Results: AR-V9 was frequently co-expressed 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% CI = 1.31-12.2, P = 0.02).   Conclusions:  AR-V9 may be an important component of therapeutic resistance in CRPC. Copyright ©2017, American Association for Cancer Research.

Journal: Clinical cancer research
DOI: 10.1158/1078-0432.CCR-17-0017
Year: 2017

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