Journal
CLINICAL CANCER RESEARCH
Volume 24, Issue 13, Pages 3149-3162Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-3571
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Funding
- Movember Foundation
- Prostate Cancer UK
- US Department of Defense
- Prostate Cancer Foundation
- Stand Up To Cancer
- Cancer Research UK
- UK Department of Health through an Experimental Cancer Medicine Centre grant
- Medical Research Council
- Academy of Medical Sciences
- MRC [MR/M018318/1] Funding Source: UKRI
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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-naive (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. (C) 2018 AACR.
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