Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells.

Resistance to available hormone therapies in prostate cancer has been associated with alternative splicing of androgen receptor (AR) and specifically, the expression of truncated and constitutively active AR variant 7 (AR-V7). The transcriptional activity of steroid receptors, including AR, is dependent on interactions with the HSP90 chaperone machinery, but it is unclear whether HSP90 modulates the activity or expression of AR variants. Here, we investigated the effects of HSP90 inhibition on AR-V7 in prostate cancer cell lines endogenously expressing this variant. We demonstrate that AR-V7 and full-length AR (AR-FL) were depleted upon inhibition of HSP90. However, the mechanisms underlying AR-V7 depletion differed from those for AR-FL. Whereas HSP90 inhibition destabilized AR-FL and induced its proteasomal degradation, AR-V7 protein exhibited higher stability than AR-FL and did not require HSP90 chaperone activity. Instead, HSP90 inhibition resulted in the reduction of AR-V7 mRNA levels but did not affect total AR transcript levels, indicating that HSP90 inhibition disrupted AR-V7 splicing. Bioinformatic analyses of transcriptome-wide RNA sequencing data confirmed that the second-generation HSP90 inhibitor onalespib altered the splicing of at least 557 genes in prostate cancer cells, including AR. These findings indicate that the effects of HSP90 inhibition on mRNA splicing may prove beneficial in prostate cancers expressing AR-V7, supporting further clinical investigation of HSP90 inhibitors in malignancies no longer responsive to androgen deprivation. Cancer Res; 76(9); 2731-42. ©2016 AACR.

Cancer research. 2016 May 01 [Epub]

Roberta Ferraldeschi, Jonathan Welti, Marissa V Powers, Wei Yuan, Tomoko Smyth, George Seed, Ruth Riisnaes, Somaieh Hedayat, Hannah Wang, Mateus Crespo, Daniel Nava Rodrigues, Ines Figueiredo, Susana Miranda, Suzanne Carreira, John F Lyons, Swee Sharp, Stephen R Plymate, Gerhardt Attard, Nicola Wallis, Paul Workman, Johann S de Bono

Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom. Prostate Cancer Targeted Therapies Group, Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Astex Pharmaceuticals, Cambridge, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Astex Pharmaceuticals, Cambridge, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Department of Medicine, University of Washington School of Medicine and GRECC at VAPSHCS Seattle, Washington. Department of Urology, University of Washington School of Medicine and GRECC at VAPSHCS Seattle, Washington., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom. Prostate Cancer Targeted Therapies Group, Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom., Astex Pharmaceuticals, Cambridge, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom., Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, United Kingdom. Prostate Cancer Targeted Therapies Group, Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom. .

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