Activation of MAPK Signaling by CXCR7 leads to enzalutamide resistance in prostate cancer

Shangze Li, Ka Wing Fong, Galina Gritsina, Ali Zhang, Jonathan C. Zhao, Jung Kim, Adam Sharp, Wei Yuan, Caterina Aversa, Ximing J. Yang, Peter S. Nelson, Felix Y. Feng, Arul M. Chinnaiyan, Johann S. De Bono, Colm Morrissey, Matthew B. Rettig, Jindan Yu

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


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 secondgeneration antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.

Original languageEnglish
Pages (from-to)2580-2592
Number of pages13
JournalCancer Research
Issue number10
StatePublished - 2019

Bibliographical note

Publisher Copyright:
© 2019 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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