TY - JOUR
T1 - Targeting Bromodomain and Extra-Terminal (BET) family proteins in Castration-Resistant Prostate Cancer (CRPC)
AU - International SU2C/PCF Prostate Cancer Dream Team
AU - Welti, Jonathan
AU - Sharp, Adam
AU - Yuan, Wei
AU - Dolling, David
AU - Rodrigues, Daniel Nava
AU - Figueiredo, Ines
AU - Gil, Veronica
AU - Neeb, Antje
AU - Clarke, Matthew
AU - Seed, George
AU - Crespo, Mateus
AU - Sumanasuriya, Semini
AU - Ning, Jian
AU - Knight, Eleanor
AU - Francis, Jeffrey C.
AU - Hughes, Ashley
AU - Halsey, Wendy S.
AU - Paschalis, Alec
AU - Mani, Ram S.
AU - Raj, Ganesh V.
AU - Plymate, Stephen R.
AU - Carreira, Suzanne
AU - Boysen, Gunther
AU - Chinnaiyan, Arul M.
AU - Swain, Amanda
AU - De Bono, Johann S.
N1 - Funding Information:
The authors would like to thank the Tissue Profiling Unit at the Institute of Cancer Research for technical assistance. GSK1210151A (I-BET151) was a kind gift from GSK. Work in the de Bono laboratory was supported by funding from the Movember Foundation, Prostate Cancer UK, US Department of Defense, the Prostate Cancer Foundation, Stand Up To Cancer, Cancer Research UK, and the UK Department of Health through an Experimental Cancer Medicine Centre grant. A. Sharp is supported by the Medical Research Council, the Academy of Medical Sciences and Prostate Cancer UK. Work in the Mani and Raj laboratories was also supported by the US Department of Defense.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - 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-na€ve (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.
AB - 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-na€ve (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.
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U2 - 10.1158/1078-0432.CCR-17-3571
DO - 10.1158/1078-0432.CCR-17-3571
M3 - Article
C2 - 29555663
AN - SCOPUS:85046288005
SN - 1078-0432
VL - 24
SP - 3149
EP - 3162
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -