Targeting Bromodomain and Extra-Terminal (BET) family proteins in Castration-Resistant Prostate Cancer (CRPC)

International SU2C/PCF Prostate Cancer Dream Team

Research output: Contribution to journalArticle

20 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)3149-3162
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number13
DOIs
StatePublished - Jul 1 2018

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Castration
Androgen Receptors
Prostatic Neoplasms
Proteins
Organoids
RNA
Biopsy
Growth Inhibitors
Alternative Splicing
Nuclear Proteins
Heterografts

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeting Bromodomain and Extra-Terminal (BET) family proteins in Castration-Resistant Prostate Cancer (CRPC). / International SU2C/PCF Prostate Cancer Dream Team.

In: Clinical Cancer Research, Vol. 24, No. 13, 01.07.2018, p. 3149-3162.

Research output: Contribution to journalArticle

International SU2C/PCF Prostate Cancer Dream Team. / Targeting Bromodomain and Extra-Terminal (BET) family proteins in Castration-Resistant Prostate Cancer (CRPC). In: Clinical Cancer Research. 2018 ; Vol. 24, No. 13. pp. 3149-3162.
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title = "Targeting Bromodomain and Extra-Terminal (BET) family proteins in Castration-Resistant Prostate Cancer (CRPC)",
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-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.",
author = "{International SU2C/PCF Prostate Cancer Dream Team} and Jonathan Welti and Adam Sharp and Wei Yuan and David Dolling and Rodrigues, {Daniel Nava} and Ines Figueiredo and Veronica Gil and Antje Neeb and Matthew Clarke and George Seed and Mateus Crespo and Semini Sumanasuriya and Jian Ning and Eleanor Knight and Francis, {Jeffrey C.} and Ashley Hughes and Halsey, {Wendy S.} and Alec Paschalis and Mani, {Ram S.} and Raj, {Ganesh V.} and Plymate, {Stephen R.} and Suzanne Carreira and Gunther Boysen and Chinnaiyan, {Arul M.} and Amanda Swain and {De Bono}, {Johann S.}",
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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.

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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