Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration‐resistant prostate cancer models

Abstract

Previous studies have shown that increased levels of chemokine receptor CXCR7 are associated with the increased invasiveness of prostate cancer cells. We now show that CXCR7 expression is upregulated in VCaP and C4‐2B cells after enzalutamide (ENZ) treatment. ENZ treatment induced apoptosis (sub‐G1) in VCaP and C4‐2B cells, and this effect was further increased after combination treatment with ENZ and CCX771, a specific CXCR7 inhibitor. The levels of p‐EGFR (Y1068), p‐AKT (T308) and VEGFR2 were reduced after ENZ and CCX771 combination treatment compared to single agent treatment. In addition, significantly greater reductions in migration were shown after combination treatment compared to those of single agents or vehicle controls, and importantly, similar reductions in the levels of secreted VEGF were also demonstrated. Orthotopic VCaP xenograft growth and subcutaneous MDA133‐4 patient‐derived xenograft (PDX) tumor growth was reduced by single agent treatment, but significantly greater suppression was observed in the combination treatment group. Although overall microvessel densities in the tumor tissues were not different among the different treatment groups, a significant reduction in large blood vessels (>100 μm2) was observed in tumors following combination treatment. Apoptotic indices in tumor tissues were significantly increased following combination treatment compared with vehicle control‐treated tumor tissues. Our results demonstrate that significant tumor suppression mediated by ENZ and CXCR7 combination treatment may be due, in part, to reductions in proangiogenic signaling and in the formation of large blood vessels in prostate cancer tumors.

Cytokines and Chemokines as Mediators of Prostate Cancer Metastasis

“…Indeed, knocking down CXCR7 in enzalutamide-resistant prostate cancer cells resulted in diminished invasiveness and tumor growth [ 211 ]. A similar phenomena was described by Luo et al [ 213 ] wherein co-treatment of enzalutamide and a CXCR7 inhibitor significantly decreased migration, VEGF secretion, and tumor growth in castration-resistant C4-2B and VCaP cells.…”

Activation of MAPK Signaling by CXCR7 Leads to Enzalutamide Resistance in Prostate Cancer

“…Many attempts have been made to generate CXCR7 antagonists with CCX771 being the most prominent. However, recent studies have unfortunately determined that CCX771, despite its ability to bind CXCL12, actually acts as an agonist (38), which raises concerns regarding studies using CCX771 as CXCR7 antagonist (39). Here, we took advantage of the readily available MAPK inhibitors to block CXCR7 downstream pathways.…”

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

“…CXCR7 promotes resistance to the TKI osimertinib in non-small-cell lung cancer (NSCLC) [ 49 ]. CXCR7 overexpression has recently been linked to acquired enzalutamide resistance in prostate cancer [ 50 ]. CXCR7 is ubiquitously overexpressed in acquired EGFR TKI resistant cell line NSCLC models with an epithelial–mesenchymal transition (EMT) phenotype [ 49 ].…”