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dc.contributor.authorLi, Yen_US
dc.contributor.authorYang, Ren_US
dc.contributor.authorHenzler, CMen_US
dc.contributor.authorHo, Yen_US
dc.contributor.authorPassow, Cen_US
dc.contributor.authorAuch, Ben_US
dc.contributor.authorCarreira, Sen_US
dc.contributor.authorNava Rodrigues, Den_US
dc.contributor.authorBertan, Cen_US
dc.contributor.authorHwang, THen_US
dc.contributor.authorQuigley, DAen_US
dc.contributor.authorDang, HXen_US
dc.contributor.authorMorrissey, Cen_US
dc.contributor.authorFraser, Men_US
dc.contributor.authorPlymate, SRen_US
dc.contributor.authorMaher, CAen_US
dc.contributor.authorFeng, FYen_US
dc.contributor.authorde Bono, JSen_US
dc.contributor.authorDehm, SMen_US
dc.date.accessioned2020-03-04T15:32:56Z
dc.date.issued2020-04en_US
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2020, 26 (8), pp. 1965 - 1976en_US
dc.identifier.issn1078-0432en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3531
dc.identifier.doi10.1158/1078-0432.ccr-19-3023en_US
dc.description.abstractPURPOSE:Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC. EXPERIMENTAL DESIGN:We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the AR locus. We used genome engineering to perform experimental modeling of AR gene rearrangements and long-read RNA sequencing to analyze effects on expression of AR and truncated AR variants (AR-V). RESULTS:AR was among the most frequently rearranged genes in CRPC tumors. AR gene rearrangements promoted expression of diverse AR-V species. AR gene rearrangements occurring in the context of AR amplification correlated with AR overexpression. Cell lines with experimentally derived AR gene rearrangements displayed high expression of tumor-specific AR-Vs and were resistant to endocrine therapies, including the AR antagonist enzalutamide. CONCLUSIONS:AR gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.en_US
dc.formatPrint-Electronicen_US
dc.format.extent1965 - 1976en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.titleDiverse AR Gene Rearrangements Mediate Resistance to Androgen Receptor Inhibitors in Metastatic Prostate Cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2020-01-09en_US
rioxxterms.versionofrecord10.1158/1078-0432.ccr-19-3023en_US
rioxxterms.licenseref.startdate2020-04en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Researchen_US
pubs.issue8en_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/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-statusPublisheden_US
pubs.volume26en_US
pubs.embargo.termsNot knownen_US
icr.researchteamCancer Biomarkersen_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
dc.contributor.icrauthorCarreira, Suzanneen_US
dc.contributor.icrauthorDe Bono, Johannen_US


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