Mar 16, 2020

Targeting CXCR1 and CXCR2 to overcome radiotherapy resistance in PTEN-deficient prostate carcinoma

bioRxiv
Chris W D ArmstrongDavid J J Waugh

Abstract

Functional impairment of the tumor suppressor PTEN is common in primary prostate cancer and has been linked to relapse post-radiotherapy (RT). Pre-clinical modelling supports elevated CXC-chemokine signaling as a critical mediator of PTEN -depleted disease progression and therapeutic resistance. Our objective was to assess the correlation of PTEN -deficiency with CXC-chemokine signaling and its association with clinical outcomes. Gene expression analysis characterized a PTEN LOW/ CXCR1 HIGH/ CXCR2 HIGH cluster of tumors that associates with earlier time-to-biochemical recurrence (HR 5.87, p<0.001 and HR 2.65, p<0.001, respectively) and development of systemic metastasis (HR 3.51, p<0.001). In vitro , CXCL-signaling was further amplified following exposure of PTEN -deficient prostate cancer cell lines to ionizing radiation (IR). Inhibition of CXCR1/2-signaling in all 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 PC3, DU145 and C42 xenografts attenuated tumor growth and progression compared to control or IR alone. Post-mortem analysis confirmed that x1/2pal-i3 adminis...Continue Reading

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Mentioned in this Paper

CXC Chemokines
CXCL1
Complement C5 Convertase, Classical Pathway
Present
PTEN protein, human
Interleukin-8B Receptor
Malignant Neoplasm of Prostate
Tumor Suppressor Genes
Interleukin 8A Receptor
Intermediate Oculomotor Nucleus

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