Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma.

Functional impairment of the tumour suppressor is common in primary prostate cancer and has been linked to relapse post-radiotherapy (post-RT). Pre-clinical modelling supports elevated CXC chemokine signalling as a critical mediator of -depleted disease progression and therapeutic resistance. We assessed the correlation of deficiency with CXC chemokine signalling and its association with clinical outcomes. Gene expression analysis characterized a /CXCR1/CXCR2 cluster of tumours that associates with earlier time to biochemical recurrence [hazard ratio (HR) 5.87 and 2.65, respectively] and development of systemic metastasis (HR 3.51). , CXCL signalling was further amplified following exposure of -deficient prostate cancer cell lines to ionizing radiation (IR). Inhibition of CXCR1/2 signalling in depleted cell-based models increased IR sensitivity. , administration of a CXCR1/2-targeted pepducin (x1/2pal-i3), or CXCR2-specific antagonist (AZD5069), in combination with IR to -deficient xenografts attenuated tumour growth and progression compared to control or IR alone. Post-mortem analysis confirmed that x1/2pal-i3 administration attenuated IR-induced CXCL signalling and anti-apoptotic protein expression. Interventions targeting CXC chemokine signalling may provide an effective strategy to combine with RT in locally advanced prostate cancer patients with known presence of -deficient foci.