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dc.contributor.authorLi, X
dc.contributor.authorBaek, G
dc.contributor.authorCarreira, S
dc.contributor.authorYuan, W
dc.contributor.authorMa, S
dc.contributor.authorHofstad, M
dc.contributor.authorLee, S
dc.contributor.authorGao, Y
dc.contributor.authorBertan, C
dc.contributor.authorFenor de la Maza, MDLD
dc.contributor.authorAlluri, PG
dc.contributor.authorBurma, S
dc.contributor.authorChen, BP
dc.contributor.authorRaj, GV
dc.contributor.authorde Bono, J
dc.contributor.authorPommier, Y
dc.contributor.authorMani, RS
dc.coverage.spatialUnited States
dc.date.accessioned2022-07-19T10:27:50Z
dc.date.available2022-07-19T10:27:50Z
dc.date.issued2022-05-09
dc.identifier152955
dc.identifier.citationJCI Insight, 2022, 7 (9), pp. e152955 -en_US
dc.identifier.issn2379-3708
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5245
dc.identifier.eissn2379-3708
dc.identifier.eissn2379-3708
dc.identifier.doi10.1172/jci.insight.152955
dc.description.abstractThe bromodomain and extraterminal (BET) family of chromatin reader proteins bind to acetylated histones and regulate gene expression. The development of BET inhibitors (BETi) has expanded our knowledge of BET protein function beyond transcriptional regulation and has ushered several prostate cancer (PCa) clinical trials. However, BETi as a single agent is not associated with antitumor activity in patients with castration-resistant prostate cancer (CRPC). We hypothesized novel combinatorial strategies are likely to enhance the efficacy of BETi. By using PCa patient-derived explants and xenograft models, we show that BETi treatment enhanced the efficacy of radiation therapy (RT) and overcame radioresistance. Mechanistically, BETi potentiated the activity of RT by blocking DNA repair. We also report a synergistic relationship between BETi and topoisomerase I (TOP1) inhibitors (TOP1i). We show that the BETi OTX015 synergized with the new class of synthetic noncamptothecin TOP1i, LMP400 (indotecan), to block tumor growth in aggressive CRPC xenograft models. Mechanistically, BETi potentiated the antitumor activity of TOP1i by disrupting replication fork stability. Longitudinal analysis of patient tumors indicated that TOP1 transcript abundance increased as patients progressed from hormone-sensitive prostate cancer to CRPC. TOP1 was highly expressed in metastatic CRPC, and its expression correlated with the expression of BET family genes. These studies open new avenues for the rational combinatorial treatment of aggressive PCa.
dc.formatElectronic
dc.format.extente152955 -
dc.languageeng
dc.language.isoengen_US
dc.publisherAMER SOC CLINICAL INVESTIGATION INCen_US
dc.relation.ispartofJCI Insight
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCancer
dc.subjectOncology
dc.subjectRadiation therapy
dc.subjectUrology
dc.subjectCell Cycle Proteins
dc.subjectCell Line, Tumor
dc.subjectHistones
dc.subjectHumans
dc.subjectMale
dc.subjectProstatic Neoplasms, Castration-Resistant
dc.subjectTranscription Factors
dc.titleTargeting radioresistance and replication fork stability in prostate cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2022-03-24
dc.date.updated2022-07-19T10:27:08Z
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1172/jci.insight.152955en_US
rioxxterms.licenseref.startdate2022-05-09
rioxxterms.typeJournal Article/Reviewen_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/35349486
pubs.issue9
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 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.publication-statusPublished online
pubs.volume7
icr.researchteamCancer Biomarkersen_US
icr.researchteamPrCa Targeted Therapyen_US
dc.contributor.icrauthorCarreira, Suzanne
dc.contributor.icrauthorDe Bono, Johann
icr.provenanceDeposited by Mr Arek Surman on 2022-07-19. Deposit type is initial. No. of files: 1. Files: Targeting radioresistance and replication fork stability in prostate cancer.pdf


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