dc.contributor.author | Liang, Y | |
dc.contributor.author | Jeganathan, S | |
dc.contributor.author | Marastoni, S | |
dc.contributor.author | Sharp, A | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Marcellus, R | |
dc.contributor.author | Mawson, A | |
dc.contributor.author | Shalev, Z | |
dc.contributor.author | Pesic, A | |
dc.contributor.author | Sweet, J | |
dc.contributor.author | Guo, H | |
dc.contributor.author | Uehling, D | |
dc.contributor.author | Gurel, B | |
dc.contributor.author | Neeb, A | |
dc.contributor.author | He, HH | |
dc.contributor.author | Montgomery, B | |
dc.contributor.author | Koritzinsky, M | |
dc.contributor.author | Oakes, S | |
dc.contributor.author | de Bono, JS | |
dc.contributor.author | Gleave, M | |
dc.contributor.author | Zoubeidi, A | |
dc.contributor.author | Wouters, BG | |
dc.contributor.author | Joshua, AM | |
dc.date.accessioned | 2021-04-07T14:20:05Z | |
dc.date.available | 2021-04-07T14:20:05Z | |
dc.date.issued | 2021-04-15 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2021 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4496 | |
dc.identifier.eissn | 1557-3265 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-20-3260 | |
dc.description.abstract | PURPOSE: Although enzalutamide (ENZ) has been widely used to treat de novo 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. EXPERIMENTAL DESIGN: 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 in vitro and in vivo, and used knockdown and overexpression assays to study the dependencies in ENZ-resistant prostate cancer. RESULTS: ABT199 (BCL-2 inhibitor) and IMD0354 (IKKB inhibitor) were identified as potent and selective inhibitors of cell viability in ENZ-resistant cell lines in vitro and in vivo 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. CONCLUSIONS: Our findings identify BCL-2 and IKKB dependencies in clinically relevant ENZ-resistant prostate cancer cells in vitro and in vivo, but indicate that IKKB upregulation appears to have greater relevance to the progression of human castrate-resistant prostate cancer. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.title | Emergence of Enzalutamide Resistance in Prostate Cancer is Associated with BCL-2 and IKKB Dependencies. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-02-02 | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-20-3260 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2021-02-04 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
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/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
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-status | Published | |
pubs.embargo.terms | Not known | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
dc.contributor.icrauthor | Sharp, Adam | |
dc.contributor.icrauthor | Gurel, Bora | |
dc.contributor.icrauthor | De Bono, Johann | |