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dc.contributor.authorGil, V
dc.contributor.authorMiranda, S
dc.contributor.authorRiisnaes, R
dc.contributor.authorGurel, B
dc.contributor.authorD'Ambrosio, M
dc.contributor.authorVasciaveo, A
dc.contributor.authorCrespo, M
dc.contributor.authorFerreira, A
dc.contributor.authorBrina, D
dc.contributor.authorTroiani, M
dc.contributor.authorSharp, A
dc.contributor.authorSheehan, B
dc.contributor.authorChristova, R
dc.contributor.authorSeed, G
dc.contributor.authorFigueiredo, I
dc.contributor.authorLambros, M
dc.contributor.authorDolling, D
dc.contributor.authorRekowski, J
dc.contributor.authorAlajati, A
dc.contributor.authorClarke, M
dc.contributor.authorPereira, R
dc.contributor.authorFlohr, P
dc.contributor.authorFowler, G
dc.contributor.authorBoysen, G
dc.contributor.authorSumanasuriya, S
dc.contributor.authorBianchini, D
dc.contributor.authorRescigno, P
dc.contributor.authorAversa, C
dc.contributor.authorTunariu, N
dc.contributor.authorGuo, C
dc.contributor.authorPaschalis, A
dc.contributor.authorBertan, C
dc.contributor.authorBuroni, L
dc.contributor.authorNing, J
dc.contributor.authorCarreira, S
dc.contributor.authorWorkman, P
dc.contributor.authorSwain, A
dc.contributor.authorCalifano, A
dc.contributor.authorShen, MM
dc.contributor.authorAlimonti, A
dc.contributor.authorNeeb, A
dc.contributor.authorWelti, J
dc.contributor.authorYuan, W
dc.contributor.authorde Bono, J
dc.contributor.authorPCF/SU2C International Prostate Cancer Dream Team
dc.date.accessioned2022-02-03T11:25:36Z
dc.date.available2022-02-03T11:25:36Z
dc.identifier.citationCancer research, 2021, 81 (24), pp. 6207 - 6218en_US
dc.identifier.issn0008-5472
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4999
dc.identifier.eissn1538-7445en_US
dc.identifier.eissn1538-7445
dc.identifier.doi10.1158/0008-5472.can-21-3360en_US
dc.identifier.doi10.1158/0008-5472.can-21-3360
dc.description.abstractIt has been recognized for decades that ERBB signaling is important in prostate cancer, but targeting ERBB receptors as a therapeutic strategy for prostate cancer has been ineffective clinically. However, we show here that membranous HER3 protein is commonly highly expressed in lethal prostate cancer, associating with reduced time to castration resistance (CR) and survival. Multiplex immunofluorescence indicated that the HER3 ligand NRG1 is detectable primarily in tumor-infiltrating myelomonocytic cells in human prostate cancer; this observation was confirmed using single-cell RNA sequencing of human prostate cancer biopsies and murine transgenic prostate cancer models. In castration-resistant prostate cancer (CRPC) patient-derived xenograft organoids with high HER3 expression as well as mouse prostate cancer organoids, recombinant NRG1 enhanced proliferation and survival. Supernatant from murine bone marrow-derived macrophages and myeloid-derived suppressor cells promoted murine prostate cancer organoid growth <i>in vitro</i>, which could be reversed by a neutralizing anti-NRG1 antibody and ERBB inhibition. Targeting HER3, especially with the HER3-directed antibody-drug conjugate U3-1402, exhibited antitumor activity against HER3-expressing prostate cancer. Overall, these data indicate that HER3 is commonly overexpressed in lethal prostate cancer and can be activated by NRG1 secreted by myelomonocytic cells in the tumor microenvironment, supporting HER3-targeted therapeutic strategies for treating HER3-expressing advanced CRPC. SIGNIFICANCE: HER3 is an actionable target in prostate cancer, especially with anti-HER3 immunoconjugates, and targeting HER3 warrants clinical evaluation in prospective trials.en_US
dc.formatPrint-Electronicen_US
dc.format.extent6207 - 6218en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.subjectPCF/SU2C International Prostate Cancer Dream Teamen_US
dc.subjectOrganoidsen_US
dc.subjectTumor Cells, Cultureden_US
dc.subjectAnimalsen_US
dc.subjectMice, Inbred NODen_US
dc.subjectHumansen_US
dc.subjectMice, SCIDen_US
dc.subjectProstatic Neoplasmsen_US
dc.subjectCamptothecinen_US
dc.subjectReceptor, erbB-3en_US
dc.subjectNeuregulin-1en_US
dc.subjectPrognosisen_US
dc.subjectSurvival Rateen_US
dc.subjectFollow-Up Studiesen_US
dc.subjectProspective Studiesen_US
dc.subjectXenograft Model Antitumor Assaysen_US
dc.subjectApoptosisen_US
dc.subjectCell Proliferationen_US
dc.subjectMaleen_US
dc.subjectTumor Microenvironmenten_US
dc.subjectAntibodies, Monoclonal, Humanizeden_US
dc.subjectBiomarkers, Tumoren_US
dc.subjectAntineoplastic Agents, Immunologicalen_US
dc.titleHER3 Is an Actionable Target in Advanced Prostate Cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2021-10-25
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1158/0008-5472.can-21-3360en_US
dc.relation.isPartOfCancer researchen_US
pubs.issue24en_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/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology
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/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/20/21 Starting Cohort
pubs.publication-statusPublisheden_US
pubs.volume81en_US
pubs.embargo.termsNot knownen_US
icr.researchteamSignal Transduction & Molecular Pharmacology
icr.researchteamCancer Biomarkers
icr.researchteamProstate Cancer Targeted Therapy Group
icr.researchteamTranslational Therapeutics
dc.contributor.icrauthorCarreira, Suzanneen_US
dc.contributor.icrauthorWorkman, Paulen_US
dc.contributor.icrauthorDe Bono, Johannen_US
dc.contributor.icrauthorMiranda, Susanaen_US
dc.contributor.icrauthorTunariu, Ninaen_US
dc.contributor.icrauthorGurel, Boraen_US
dc.contributor.icrauthorGuo, Wei Yuen_US
dc.contributor.icrauthorSharp, Adamen_US


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Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by-nc-nd/4.0/