Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer.
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Date
2019-05-15Author
Li, S
Fong, K-W
Gritsina, G
Zhang, A
Zhao, JC
Kim, J
Sharp, A
Yuan, W
Aversa, C
Yang, XJ
Nelson, PS
Feng, FY
Chinnaiyan, AM
de Bono, JS
Morrissey, C
Rettig, MB
Yu, J
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Animals
Mice, Inbred BALB C
Humans
Mice
Mice, Nude
Neoplasm Invasiveness
Phenylthiohydantoin
Pyridones
Pyrimidinones
Antineoplastic Agents
Xenograft Model Antitumor Assays
Cell Division
Cell Survival
MAP Kinase Signaling System
Drug Resistance, Neoplasm
Male
Receptors, CXCR
HEK293 Cells
Prostatic Neoplasms, Castration-Resistant
Research team
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Language
eng
Date accepted
2019-03-29
License start date
2019-05
Citation
Cancer research, 2019, 79 (10), pp. 2580 - 2592
Publisher
AMER ASSOC CANCER RESEARCH