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.
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Nature communications. 2016 Jan 29*** epublish ***
Christine Henzler, Yingming Li, Rendong Yang, Terri McBride, Yeung Ho, Cynthia Sprenger, Gang Liu, Ilsa Coleman, Bryce Lakely, Rui Li, Shihong Ma, Sean R Landman, Vipin Kumar, Tae Hyun Hwang, Ganesh V Raj, Celestia S Higano, Colm Morrissey, Peter S Nelson, Stephen R Plymate, Scott M Dehm
Minnesota Supercomputing Institute, University of Minnesota, 117 Pleasant Street Southeast, Minneapolis, Minnesota 55455, USA., Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455, USA., Division of Gerontology and Geriatric Medicine, University of Washington, Seattle, Washington 98104, USA., Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA., Department of Urology, University of Washington, 1959 Northeast Pacific Street, Box 356510, Seattle, Washington 98195, USA., Department of Urology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA., Department of Computer Science and Engineering, University of Minnesota, 200 Union Street Southeast, Minneapolis, Minnesota 55455, USA., Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, 2201 Inwood Road, Dallas, Texas 75390, USA.