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dc.contributor.authorLi, S
dc.contributor.authorFong, K-W
dc.contributor.authorGritsina, G
dc.contributor.authorZhang, A
dc.contributor.authorZhao, JC
dc.contributor.authorKim, J
dc.contributor.authorSharp, A
dc.contributor.authorYuan, W
dc.contributor.authorAversa, C
dc.contributor.authorYang, XJ
dc.contributor.authorNelson, PS
dc.contributor.authorFeng, FY
dc.contributor.authorChinnaiyan, AM
dc.contributor.authorde Bono, JS
dc.contributor.authorMorrissey, C
dc.contributor.authorRettig, MB
dc.contributor.authorYu, J
dc.date.accessioned2020-11-03T14:58:06Z
dc.date.issued2019-05
dc.identifier.citationCancer research, 2019, 79 (10), pp. 2580 - 2592
dc.identifier.issn0008-5472
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4206
dc.identifier.eissn1538-7445
dc.identifier.doi10.1158/0008-5472.can-18-2812
dc.description.abstractCastration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed CXCR7 by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth in vitro and in vivo . Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. SIGNIFICANCE: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to second-generation antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.
dc.formatPrint-Electronic
dc.format.extent2580 - 2592
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectMice, Inbred BALB C
dc.subjectHumans
dc.subjectMice
dc.subjectMice, Nude
dc.subjectNeoplasm Invasiveness
dc.subjectPhenylthiohydantoin
dc.subjectPyridones
dc.subjectPyrimidinones
dc.subjectAntineoplastic Agents
dc.subjectXenograft Model Antitumor Assays
dc.subjectCell Division
dc.subjectCell Survival
dc.subjectMAP Kinase Signaling System
dc.subjectDrug Resistance, Neoplasm
dc.subjectMale
dc.subjectReceptors, CXCR
dc.subjectHEK293 Cells
dc.subjectProstatic Neoplasms, Castration-Resistant
dc.titleActivation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer.
dc.typeJournal Article
dcterms.dateAccepted2019-03-29
rioxxterms.versionofrecord10.1158/0008-5472.can-18-2812
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer research
pubs.issue10
pubs.notesNot 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/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics
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/Primary Group/ICR Divisions/Clinical Studies/Translational Therapeutics
pubs.publication-statusPublished
pubs.volume79
pubs.embargo.termsNot known
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
icr.researchteamTranslational Therapeuticsen_US
dc.contributor.icrauthorSharp, Adamen
dc.contributor.icrauthorDe Bono, Johannen


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