期刊
CANCER RESEARCH
卷 79, 期 10, 页码 2580-2592出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-2812
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资金
- American Cancer Society [RSG-12-085-01, IRG-18-163-24]
- Department of Defense [PC160328]
- NIH [R01CA172384, R50CA211271, P50CA180995, P50CA097186, T32CA09560, T32DK007169]
- Prostate Cancer Foundation [2017CHAL2008]
- Movember Foundation
- Prostate Cancer UK
- US Department of Defense
- Prostate Cancer Foundation
- UK Department of Health through an Experimental Cancer Medicine Centre grant
- Medical Research Council
- Academy of Medical Sciences
- Stand Up To Cancer-Prostate Cancer DreamTeamTranslational Research Grant [SU2C-AACR-DT0712]
- MRC [MR/M018318/1] Funding Source: UKRI
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 beta-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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