Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer
Authors: Ali Zhang
Caterina Aversa
Felix Y Feng
Jung Kim
Ka-Wing Fong
Ximing J Yang
Colm Morrissey
Adam Sharp
Johann S de Bono
Galina Gritsina
Arul M Chinnaiyan
Peter S Nelson
Jindan Yu
Wei Yuan
Jonathan C Zhao
Shangze Li
Matthew B Rettig
Journal: Cancer research (2019)
Discipline: CLINICAL MEDICINE
Keywords: Castration-resistant prostate cancer; Enzalutamide resistance; CXCR7; Androgen receptor; MAPK/ERK signaling
Affiliations: Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Institute of Cancer Research, London, United Kingdom., Royal Marsden Hospital, London, United Kingdom., Department of Pathology, Northwestern University, Chicago, Illinois., Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois., Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington., Departments of Radiation Oncology, Urology, and Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California., Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan., Department of Urology, University of Washington, Seattle, Washington., Department of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California., VA Greater Los Angeles Healthcare System, Los Angeles, California., Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. .

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 Œ≤-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. 

Retracted: No

PubPeer comments:
 Why is the same image used three times in Figure 5j?  , 
 2020 correction. https: cancerres.aacrjournals.org content 80 10 2072 In the original version of this article (1), the same image was inadvertently duplicated in Fig. 5J, column #2. These errors have been corrected in the latest online HTML and PDF versions of the article. The authors regret this error. Reference 1.u21b5Li S, Fong K, Gritsina G, Zhang A, Zhao J, Kim J, et al. Activation of MAP ,