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

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    Authors
    Armstrong, C. W. D.
    Coulter, J. A.
    Ong, C. W.
    Maxwell, P. J.
    Walker, S.
    Butterworth, K. T.
    Lyubomska, O.
    Berlingeri, S.
    Gallagher, R.
    O'Sullivan, J. M.
    Jain, S.
    Mills, I. G.
    Prise, K. M.
    Bristow, Robert G
    LaBonte, M. J.
    Waugh, D. J. J.
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    Affiliation
    Movember FASTMAN Centre of Excellence, Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast BT9 7AE, UK.
    Issue Date
    2020
    
    Metadata
    Show full item record
    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/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.
    Citation
    Armstrong CWD, Coulter JA, Ong CW, Maxwell PJ, Walker S, Butterworth KT, et al. Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma. NAR Cancer. 2020;2(3):zcaa012.
    Journal
    NAR Cancer
    URI
    http://hdl.handle.net/10541/623224
    DOI
    10.1093/narcan/zcaa012
    PubMed ID
    32743555
    Additional Links
    https://dx.doi.org/10.1093/narcan/zcaa012
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1093/narcan/zcaa012
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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