Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC.
Bibliographical noteFunding Information:
We thank the patients and their families who were willing to participate in the Prostate Cancer Donor Program. We acknowledge Drs Robert Vessella, Bruce Montgomery, Evan Yu, Elahe Mostaghel, Heather Cheng, Paul Lange, Martine Roudier and Lawrence True, and the tissue acquisition teams for their contributions to the University of Washington Prostate Cancer Donor Program. In addition, we thank Dr Eva Corey for access to LuCaP xenograft tissue and Belinda Nghiem for her technical expertise. This research was supported by funding from NIH grants R01CA174777 (to S.M.D.), U.S. Department of Defense Prostate Cancer Research Program Transformative Impact Award W81XWH-15-1-0430 (to S.R.P. and S.M.D.), the Pacific Northwest Prostate Cancer SPORE (P50CA97186 to P.S.N.), PO1 NIH grants (PO1CA085859 and PO1CA163227) and the Richard M. Lucas Foundation. T.M. was supported by NIH Medical Scientist Training Program grant T32GM008244.
© 2016 The Author(s).