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Sensitizing Ewing sarcoma to chemo- and radiotherapy by inhibition of the DNA-repair enzymes DNA protein kinase (DNA-PK) and poly-ADP-ribose polymerase (PARP) 1/2

Lookup NU author(s): Dr Britta Vormoor, Yvonne Schlosser, Dr Helen Blair, Abhishek Sharma, Sarah Wilkinson, Emeritus Professor Herbie Newell, Professor Nicola Curtin

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© Vormoor et al. Background: DNA-PK and PARP inhibitors sensitize cancer cells to chemo- and radiotherapy. ETS transcription factors (EWS-FLI1) have been described as biomarkers for PARP-inhibitor sensitivity. Sensitivity to single agent PARP inhibitors has so far been limited to homologous recombination repair (HRR) deficient tumors, exploiting synthetic lethality. Results: In clonogenic assays, single agent rucaparib LD50 values for continuously exposed cells were similar to those observed in HRR-defective cells (CAPAN-1 cell line, BRCA2 defective); however, both ES cell lines (TC-71, CADO-ES1) had functional HRR. In vivo rucaparib administration (10 mg/kg daily) showed no responses. In clonogenic assays, rucaparib enhanced temozolomide, camptothecin and radiation cytotoxicity, which was most profound for temozolomide (15-29 fold enhancement). NU7441 increased the cytotoxicity of etoposide, doxorubicin and radiation. Materials and Methods: We assessed PARP1/2 (rucaparib) and DNA-PK (NU7441) inhibitors in Ewing sarcoma (ES) cell lines by performing growth inhibition and clonogenic assays. HRR was measured by RAD51 focus formation. Single agent rucaparib was assessed in an in vivo orthotopic model. Conclusions: Single agent rucaparib ES sensitivity in vitro was not replicated in vivo. DNA-PK and PARP inhibitors are good chemo-/radiosensitizers in ES. The future of these inhibitors lies in their combination with chemo-/radiotherapy, which needs to be evaluated in clinical trials.


Publication metadata

Author(s): Vormoor B, Schlosser YT, Blair H, Sharma A, Wilkinson S, Newell DR, Curtin N

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2017

Volume: 8

Issue: 69

Pages: 113418-113430

Online publication date: 28/09/2017

Acceptance date: 16/09/2017

Date deposited: 11/01/2018

ISSN (electronic): 1949-2553

Publisher: Impact Journals LLC

URL: https://doi.org/10.18632/oncotarget.21300

DOI: 10.18632/oncotarget.21300


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