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 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. Experimental Design: 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. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 30 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 ¼ 4.0; 95% confidence interval, 1.31–12.2; P ¼ 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC.
Bibliographical noteFunding Information:
We thank all patients who participated in this study for their selfless contribution in bringing precision medicine to future advanced prostate cancer patients. We appreciate the support of family members as well. We gratefully acknowledge the recruitment efforts of the following physicians who made patient referrals to the PROMOTE program: Sandeep Basu (Mayo Clinic Health Systems), Daniel Burns (Mayo Clinic Health Systems), Kevin Cockerill (Mayo Clinic Health Systems), Alan H. Bryce (Mayo Clinic, Arizona), Sarah Kratz (Mayo Clinic Health Systems), Mohammad Ranginwala (Mayo Clinic Health Systems), Amrit Singh (Mayo Clinic Health Systems), Gautam Jha (University of Minnesota), Badrinath Konety (University of Minnesota), Mir Ali Khan (CGH Medical Center), Ferdinand Addo (Prairie Lakes Healthcare System), Kevin Panico (Altru Health System), and Laura Joque (Essentia Health Brainerd Clinic). We also acknowledge the University of Wisconsin Carbone Cancer Center genitourinary clinical research group. Other contributing groups include the Mayo Clinic Cancer Center, the Pharmacogenomics Research Network (PGRN), A.T. Suharya and Ghan D.H., Joseph and Gail Gassner, Mayo Clinic Schulze Center for Novel Therapeutics in Cancer Research, and the Apogee
Development of methodology: M. Kohli, Y. Ho, J.L. Van Etten, T. Hon, H. Sicotte, J. Jen, S.M. Dehm Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M. Kohli, Y. Ho, J.M. Sperger, Y. Li, T. Hon, T. Clark, W. Tan, H. Sicotte, H. Thai, R. Jimenez, B.W. Eckloff, H.C. Pitot, B.A. Costello, J. Jen, E.D. Wieben, J.M. Lang, L. Wang Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): M. Kohli, D.W. Hillman, C. Henzler, R. Yang, J.M. Sperger, Y. Li, W. Tan, R.E. Carlson, L. Wang, H. Sicotte, H. Thai, P.T. Vedell, E.D. Wieben, J.M. Lang, S.M. Dehm Writing,review,and/orrevisionofthemanuscript:M.Kohli,Y.Ho,D.W.Hillman, E.Tseng, T.Clark,W.Tan,H.Sicotte,H.Thai,R.Jimenez,H.Huang,H.C.Pitot,B.A. Costello, J. Jen, E.D. Wieben, K.A.T. Silverstein, J.M. Lang, L. Wang, S.M. Dehm
R. Jimenez is an employee of Histowiz. J.M. Lang has ownership interests (including patents) in Salus Discovery, LLC and is a consultant/advisory board member for Sanofi. S.M. Dehm is a consultant/advisory board member for Astellas/Medivation and Janssen Research and Development LLC. No potential conflicts of interest were disclosed by the other authors.