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dc.contributor.authorLiang, Y
dc.contributor.authorJeganathan, S
dc.contributor.authorMarastoni, S
dc.contributor.authorSharp, A
dc.contributor.authorFigueiredo, I
dc.contributor.authorMarcellus, R
dc.contributor.authorMawson, A
dc.contributor.authorShalev, Z
dc.contributor.authorPesic, A
dc.contributor.authorSweet, J
dc.contributor.authorGuo, H
dc.contributor.authorUehling, D
dc.contributor.authorGurel, B
dc.contributor.authorNeeb, A
dc.contributor.authorHe, HH
dc.contributor.authorMontgomery, B
dc.contributor.authorKoritzinsky, M
dc.contributor.authorOakes, S
dc.contributor.authorde Bono, JS
dc.contributor.authorGleave, M
dc.contributor.authorZoubeidi, A
dc.contributor.authorWouters, BG
dc.contributor.authorJoshua, AM
dc.date.accessioned2021-04-07T14:20:05Z
dc.date.available2021-04-07T14:20:05Z
dc.date.issued2021-02-04
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2021en_US
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4496
dc.identifier.eissn1557-3265en_US
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-20-3260en_US
dc.identifier.doi10.1158/1078-0432.ccr-20-3260
dc.description.abstract<h4>Purpose</h4>Although enzalutamide (ENZ) has been widely used to treat <i>de novo</i> or castration-resistant metastatic prostate cancer, resistance develops and disease progression is ultimately inevitable. There are currently no approved targeted drugs to specifically delay or overcome ENZ resistance.<h4>Experimental design</h4>We selected several ENZ-resistant cell lines that replicated clinical characteristics of the majority of patients with ENZ-resistant disease. A high-throughput pharmacologic screen was utilized to identify compounds with greater cytotoxic effect for ENZ-resistant cell lines, compared with parental ENZ-sensitive cells. We validated the potential hits <i>in vitro</i> and <i>in vivo</i>, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer.<h4>Results</h4>ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines <i>in vitro</i> and <i>in vivo</i> which were further validated using loss-of-function assays of BCL-2 and IKKB. Notably, we observed that overexpression of BCL-2 and IKKB in ENZ-sensitive cell lines was sufficient for the emergence of ENZ resistance. In addition, we confirmed that BCL-2 or IKKB inhibitors suppressed the development of ENZ resistance in xenografts. However, validation of both BCL-2 and IKKB in matched castration-sensitive/resistant clinical samples showed that, concurrent with the development of ENZ/abiraterone resistance in patients, only the protein levels of IKKB were increased.<h4>Conclusions</h4>Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells <i>in vitro</i> and <i>in vivo</i>, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer.en_US
dc.formatPrint-Electronicen_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.titleEmergence of Enzalutamide Resistance in Prostate Cancer is Associated with BCL-2 and IKKB Dependencies.en_US
dc.typeJournal Article
dcterms.dateAccepted2021-02-02
rioxxterms.versionAMen_US
rioxxterms.versionofrecord10.1158/1078-0432.ccr-20-3260en_US
rioxxterms.licenseref.startdate2021-02-04
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Researchen_US
pubs.notesNot knownen_US
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.publication-statusPublisheden_US
pubs.embargo.termsNot knownen_US
icr.researchteamProstate Cancer Targeted Therapy Group
dc.contributor.icrauthorDe Bono, Johannen_US


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