Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy

O’Neill, Daniel; Jones, Dominic; Wade, Mark; Grey, James; Nakjang, Sirintra; Guo, Wenrui; Cork, David; Davies, Barry R.; Wedge, Steve R.; Robson, Craig N.; Gaughan, Luke

Abstract

The persistence of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the unmet clinical need for the development of more effective AR targeting therapies. A key mechanism of therapy-resistance is by selection of AR mutations that convert anti-androgens to agonists enabling the retention of androgenic signalling in CRPC. To improve our understanding of these receptors in advanced disease we developed a physiologically-relevant model to analyse the global functionality of AR mutants in CRPC. Using the bicalutamide-activated ARW741L/C mutation as proof of concept, we demonstrate that this mutant confers an androgenic-like signalling programme and growth promoting phenotype in the presence of bicalutamide. Transcriptomic profiling of ARW741L highlighted key genes markedly up-regulated by the mutant receptor, including TIPARP, RASD1 and SGK1. Importantly, SGK1 expression was found to be highly expressed in the KUCaP xenograft model and a CRPC patient biopsy sample both of which express the bicalutamide-activated receptor mutant. Using an SGK1 inhibitor, ARW741L transcriptional and growth promoting activity was reduced indicating that exploiting functional distinctions between receptor isoforms in our model may provide new and effective therapies for CRPC patients.

Citation

O’Neill, D., Jones, D., Wade, M., Grey, J., Nakjang, S., Guo, W., Cork, D., Davies, B. R., Wedge, S. R., Robson, C. N., & Gaughan, L. (2015). Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy. Oncotarget, 6(28), 26029-26040. https://doi.org/10.18632/oncotarget.4347

• Journal Article Type: Article
• Acceptance Date: Jul 8, 2015
• Online Publication Date: Jul 18, 2015
• Publication Date: Sep 22, 2015
• Deposit Date: Feb 4, 2019
• Publicly Available Date: Feb 5, 2019
• Journal: Oncotarget
• Print ISSN: 1949-2553
• Publisher: Impact Journals
• Peer Reviewed: Peer Reviewed
• Volume: 6
• Issue: 28
• Pages: 26029-26040
• DOI: https://doi.org/10.18632/oncotarget.4347
• Keywords: Prostate cancer; Androgen receptor; Mutation; Anti-androgen-resistance; SGK1
• Public URL: https://hull-repository.worktribe.com/output/1271261
• Publisher URL: http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=4347&pubmed-linkout=1
• Contract Date: Feb 4, 2019