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
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Britta Vormoor1,2, Yvonne T. Schlosser3, Helen Blair1, Abhishek Sharma4, Sarah Wilkinson5, David R. Newell6 and Nicola Curtin6
1Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
2Department of Paediatric and Adolescent Haematology and Oncology, Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
3German Cancer Research Center, DKFZ, Cell Cycle Control and Carcinogenesis, Heidelberg, Germany
4NORLUX Neuro-Oncology Laboratory, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
5Northumbria University, Department of Health and Life Sciences, Newcastle upon Tyne, UK
6Northern Institute for Cancer Research, Newcastle University, Paul O’Gorman Building, Newcastle upon Tyne, UK
Britta Vormoor, email: firstname.lastname@example.org
Keywords: ewing sarcoma, PARP-inhibitor, rucaparib, DNA-PK inhibitor, NU7441
Received: September 07, 2017 Accepted: September 16, 2017 Published: September 28, 2017
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.
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