dc.contributor.author | Welti, J | |
dc.contributor.author | Sharp, A | |
dc.contributor.author | Yuan, W | |
dc.contributor.author | Dolling, D | |
dc.contributor.author | Nava Rodrigues, D | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Gil, V | |
dc.contributor.author | Neeb, A | |
dc.contributor.author | Clarke, M | |
dc.contributor.author | Seed, G | |
dc.contributor.author | Crespo, M | |
dc.contributor.author | Sumanasuriya, S | |
dc.contributor.author | Ning, J | |
dc.contributor.author | Knight, E | |
dc.contributor.author | Francis, JC | |
dc.contributor.author | Hughes, A | |
dc.contributor.author | Halsey, WS | |
dc.contributor.author | Paschalis, A | |
dc.contributor.author | Mani, RS | |
dc.contributor.author | Raj, GV | |
dc.contributor.author | Plymate, SR | |
dc.contributor.author | Carreira, S | |
dc.contributor.author | Boysen, G | |
dc.contributor.author | Chinnaiyan, AM | |
dc.contributor.author | Swain, A | |
dc.contributor.author | de Bono, JS | |
dc.contributor.author | International SU2C/PCF Prostate Cancer Dream Team, | |
dc.date.accessioned | 2020-11-05T11:02:56Z | |
dc.date.issued | 2018-07-01 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2018, 24 (13), pp. 3149 - 3162 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4217 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-17-3571 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 3149 - 3162 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | International SU2C/PCF Prostate Cancer Dream Team | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Proteins | |
dc.subject | Cell Cycle Proteins | |
dc.subject | Nuclear Proteins | |
dc.subject | Protein Isoforms | |
dc.subject | Receptors, Androgen | |
dc.subject | Transcription Factors | |
dc.subject | RNA, Small Interfering | |
dc.subject | Antineoplastic Agents | |
dc.subject | Prognosis | |
dc.subject | Treatment Outcome | |
dc.subject | Gene Expression Profiling | |
dc.subject | Computational Biology | |
dc.subject | Signal Transduction | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Alternative Splicing | |
dc.subject | Male | |
dc.subject | Gene Knockdown Techniques | |
dc.subject | Molecular Targeted Therapy | |
dc.subject | Prostatic Neoplasms, Castration-Resistant | |
dc.subject | Biomarkers, Tumor | |
dc.title | Targeting Bromodomain and Extra-Terminal (BET) Family Proteins in Castration-Resistant Prostate Cancer (CRPC). | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2018-03-14 | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-17-3571 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2018-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.issue | 13 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Development & Cancer | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
pubs.publication-status | Published | |
pubs.volume | 24 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Translational Therapeutics | |
icr.researchteam | Development & Cancer | |
dc.contributor.icrauthor | Sharp, Adam | |
dc.contributor.icrauthor | Nava Rodrigues, Daniel | |
dc.contributor.icrauthor | Clarke, Matthew | |
dc.contributor.icrauthor | Seed, George | |
dc.contributor.icrauthor | Sumanasuriya, Semini | |
dc.contributor.icrauthor | Paschalis, Alec | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | Swain, Amanda | |
dc.contributor.icrauthor | De Bono, Johann | |