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Functional impairment of the tumour suppressor  PTEN  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  PTEN -depleted disease progression and therapeutic resistance. We assessed the correlation of  PTEN  deficiency with CXC chemokine signalling and its association with clinical outcomes. Gene expression analysis characterized a  PTEN  LOW /CXCR1 HIGH /CXCR2 HIGH  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).  In vitro , CXCL signalling was further amplified following exposure of  PTEN -deficient prostate cancer cell lines to ionizing radiation (IR). Inhibition of CXCR1/2 signalling in  PTEN- depleted cell-based models increased IR sensitivity.  In vivo , administration of a CXCR1/2-targeted pepducin (x1/2pal-i3), or CXCR2-specific antagonist (AZD5069), in combination with IR to  PTEN -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  PTEN -deficient foci.

nar cancer

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