Jonathan Welti 1 , Adam Sharp 1,2 , Wei Yuan 1 , David Dolling 1 , Daniel Nava Rodrigues 1 , Ines Figueiredo 1 , Veronica Gil 1 , Antje Neeb 1 , Matthew Clarke 1 , George Seed 1 , Mateus Crespo 1 , Semini Sumanasuriya 1,2 , Jian Ning 1 , Eleanor Knight 1 , Jeffrey C Francis 1 , Ashley Hughes 3 , Wendy S Halsey 3 , Alec Paschalis 1,2 , Ram S Mani 4 , Ganesh V Raj 4 , Stephen R Plymate 5 , Suzanne Carreira 1 , Gunther Boysen , Arul M Chinnaiyan 6 , Amanda Swain 1 , Johann S de Bono 7,2 Show Affiliations »
Abstract
Purpose: Persistent androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR-targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET) protein inhibitors (BETi) abrogate aberrant AR signaling in CRPC.Experimental Design: We determined associations between BET expression, AR-driven transcription, and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR-V7 expression and AR signaling in prostate cancer models.Results: Nuclear BRD4 protein expression increases significantly (P ≤ 0.01) with castration resistance in same patient treatment-naïve (median H-score; interquartile range: 100; 100-170) and CRPC (150; 110-200) biopsies, with higher expression at diagnosis associating with worse outcome (HR, 3.25; 95% CI, 1.50-7.01; P ≤ 0.001). BRD2, BRD3, and BRD4 RNA expression in CRPC biopsies correlates with AR-driven transcription (all P ≤ 0.001). Chemical BETi, and combined BET family protein knockdown, reduce AR-V7 expression and AR signaling. This was not recapitulated by C-MYC knockdown. In addition, we show that BETi regulates RNA processing thereby reducing alternative splicing and AR-V7 expression. Furthermore, BETi reduce growth of prostate cancer cells and patient-derived organoids with known AR mutations, AR amplification and AR-V7 expression. Finally, BETi, unlike enzalutamide, decreases persistent AR signaling and growth (P ≤ 0.001) of a patient-derived xenograft model of CRPC with AR amplification and AR-V7 expression.Conclusions: BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof-of-mechanism pharmacodynamic studies. Clin Cancer Res; 24(13); 3149-62. ©2018 AACR. ©2018 American Association for Cancer Research.
Purpose: Persistent androgen receptor (AR ) signaling drives castration-resistant prostate cancer (CRPC) and confers resistance to AR -targeting therapies. Novel therapeutic strategies to overcome this are urgently required. We evaluated how bromodomain and extra-terminal (BET ) protein inhibitors (BETi ) abrogate aberrant AR signaling in CRPC.Experimental Design: We determined associations between BET expression, AR -driven transcription, and patient outcome; and the effect and mechanism by which chemical BETi (JQ1 and GSK1210151A; I-BET151) and BET family protein knockdown regulates AR -V7 expression and AR signaling in prostate cancer models.Results: Nuclear BRD4 protein expression increases significantly (P ≤ 0.01) with castration resistance in same patient treatment-naïve (median H-score; interquartile range: 100; 100-170) and CRPC (150; 110-200) biopsies, with higher expression at diagnosis associating with worse outcome (HR, 3.25; 95% CI, 1.50-7.01; P ≤ 0.001). BRD2 , BRD3 , and BRD4 RNA expression in CRPC biopsies correlates with AR -driven transcription (all P ≤ 0.001). Chemical BETi , and combined BET family protein knockdown, reduce AR -V7 expression and AR signaling. This was not recapitulated by C-MYC knockdown. In addition, we show that BETi regulates RNA processing thereby reducing alternative splicing and AR -V7 expression. Furthermore, BETi reduce growth of prostate cancer cells and patient -derived organoids with known AR mutations, AR amplification and AR -V7 expression. Finally, BETi , unlike enzalutamide , decreases persistent AR signaling and growth (P ≤ 0.001) of a patient -derived xenograft model of CRPC with AR amplification and AR -V7 expression.Conclusions: BETi merit clinical evaluation as inhibitors of AR splicing and function, with trials demonstrating their blockade in proof-of-mechanism pharmacodynamic studies. Clin Cancer Res; 24(13); 3149-62. ©2018 AACR. ©2018 American Association for Cancer Research.
Entities: Chemical
Disease
Gene
Species
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Year: 2018
PMID： 29555663 DOI： 10.1158/1078-0432.CCR-17-3571
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531