dc.contributor.author | Li, S | |
dc.contributor.author | Fong, K-W | |
dc.contributor.author | Gritsina, G | |
dc.contributor.author | Zhang, A | |
dc.contributor.author | Zhao, JC | |
dc.contributor.author | Kim, J | |
dc.contributor.author | Sharp, A | |
dc.contributor.author | Yuan, W | |
dc.contributor.author | Aversa, C | |
dc.contributor.author | Yang, XJ | |
dc.contributor.author | Nelson, PS | |
dc.contributor.author | Feng, FY | |
dc.contributor.author | Chinnaiyan, AM | |
dc.contributor.author | de Bono, JS | |
dc.contributor.author | Morrissey, C | |
dc.contributor.author | Rettig, MB | |
dc.contributor.author | Yu, J | |
dc.date.accessioned | 2020-11-03T14:58:06Z | |
dc.date.issued | 2019-05-15 | |
dc.identifier.citation | Cancer research, 2019, 79 (10), pp. 2580 - 2592 | |
dc.identifier.issn | 0008-5472 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4206 | |
dc.identifier.eissn | 1538-7445 | |
dc.identifier.doi | 10.1158/0008-5472.can-18-2812 | |
dc.description.abstract | Castration-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.format | Print-Electronic | |
dc.format.extent | 2580 - 2592 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Mice, Inbred BALB C | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, Nude | |
dc.subject | Neoplasm Invasiveness | |
dc.subject | Phenylthiohydantoin | |
dc.subject | Pyridones | |
dc.subject | Pyrimidinones | |
dc.subject | Antineoplastic Agents | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Cell Division | |
dc.subject | Cell Survival | |
dc.subject | MAP Kinase Signaling System | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Male | |
dc.subject | Receptors, CXCR | |
dc.subject | HEK293 Cells | |
dc.subject | Prostatic Neoplasms, Castration-Resistant | |
dc.title | Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-03-29 | |
rioxxterms.versionofrecord | 10.1158/0008-5472.can-18-2812 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/all-rights-reserved | |
rioxxterms.licenseref.startdate | 2019-05 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer research | |
pubs.issue | 10 | |
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/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-status | Published | |
pubs.volume | 79 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
icr.researchteam | Translational Therapeutics | |
dc.contributor.icrauthor | Sharp, Adam | |
dc.contributor.icrauthor | De Bono, Johann | |