Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma. (3rd July 2020)

• Record Type: Journal Article
• Authors: Armstrong, Chris W D; Coulter, Jonathan A; Ong, Chee Wee; Maxwell, Pamela J; Walker, Steven; Butterworth, Karl T; Lyubomska, Oksana; Berlingeri, Silvia; Gallagher, Rebecca; O'Sullivan, Joe M; Jain, Suneil; Mills, Ian G; Prise, Kevin M; Bristow, Robert G; LaBonte, Melissa J; Waugh, David J J
• Is Part Of: NAR cancer. Volume 2:Number 3(2020)
• Publication Date: 2020-07-03
• Subjects: Cancer -- Periodicals; Cancer -- Genetic aspects -- Periodicals; Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 616.994
• DOI: 10.1093/narcan/zcaa012
• Languages: English
• ISSNs: 2632-8674

Abstract

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 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.