Abstract
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 PTENLOW/CXCR1HIGH/CXCR2HIGH 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.
Highlights
External beam radiotherapy (RT) constitutes a principal treatment modality for organ-confined prostate cancer (CaP) [1]
Our initial analysis was conducted using the MSKCC radical prostatectomy cohort, focusing on the 140 patients with relevant clinical follow-up data [24]. This dataset derived from radically resected tumours demonstrated that PTENLOW (P = 0.0014), CXCR1HIGH (P = 0.017) and CXCR2HIGH (P = 0.035) expression each independently correlated with accelerated biochemical recurrence (BCR; Figure 1A)
We observed that the PTENLOW and CXCR1/2HIGH tumours formed a distinct cluster or subgroup constituting 74 (52.9%) of the 140 tumours represented in this resection cohort (Figure 1B)
Summary
External beam radiotherapy (RT) constitutes a principal treatment modality for organ-confined prostate cancer (CaP) [1]. The majority of tumours respond favourably, over one-third of patients will experience relapse post-RT, which has been attributed to intrinsic radioresistance of tumour cells, release and signalling of stroma-derived survival factors or presence of occult micrometastases at the time of diagnosis [2,3,4]. The cellular response of tumour cells to DNA damage treatment can be related to an underlying genetic background and can itself markedly alter gene expression to effect differential phenotypic behaviour [5,6].
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