Inhibition of CXCR4 Enhances the Efficacy of Radiotherapy in Metastatic Prostate Cancer Models

SIMPLE SUMMARY: We examined the expression of SDF1α and its cognate receptor CXCR4 in human prostate cancer (PCa) lesions and the impact of CXCR4 inhibition alone and in combination with single-dose irradiation in orthotopic PCa models in mice. Both SDF1α and CXCR4 were highly expressed in primary and bone metastatic human PCa samples. Inhibiting CXCR4 activity in PCa cells abrogated SDF1α-induced invasion but did not sensitize them to irradiation in vitro. In orthotopic primary and bone metastatic PCa models, treatment with the CXCR4 antagonist AMD3100 alone was ineffective, but when added to radiotherapy, it significantly inhibited metastatic tumor growth. The mechanisms of AMD3100 included normalization of bone metastatic PCa vasculature. These results support testing SDF1α/CXCR4 inhibitors with radiotherapy in metastatic PCa patients. ABSTRACT: Radiotherapy (RT) is a standard treatment for patients with advanced prostate cancer (PCa). Previous preclinical studies showed that SDF1α/CXCR4 axis could mediate PCa metastasis (most often to the bones) and cancer resistance to RT. We found high levels of expression for both SDF1α and its receptor CXCR4 in primary and metastatic PCa tissue samples. In vitro analyses using PCa cells revealed an important role of CXCR4 in cell invasion but not radiotolerance. Pharmacologic inhibition of CXCR4 using AMD3100 showed no efficacy in orthotopic primary and bone metastatic PCa models. However, when combined with RT, AMD3100 potentiated the effect of local single-dose RT (12 Gy) in both models. Moreover, CXCR4 inhibition also reduced lymph node metastasis from primary PCa. Notably, CXCR4 inhibition promoted the normalization of bone metastatic PCa vasculature and reduced tissue hypoxia. In conclusion, the SDF1α/CXCR4 axis is a potential therapeutic target in metastatic PCa patients treated with RT.