Abstract
BackgroundDNA-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.ResultsIn 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 MethodsWe 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.ConclusionsSingle 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.
Highlights
The Ewing sarcoma family of tumors (ESFT) is the second most common malignant bone or soft tissue tumor in childhood and adolescence, accounting for approximately 1.5% of all pediatric cancers
In clonogenic assays, single agent rucaparib LD50 values for continuously exposed cells were similar to those observed in homologous recombination repair (HRR)-defective cells (CAPAN-1 cell line, BRCA2 defective); both ES cell lines (TC-71, CADO-ES1) had functional HRR
We report here preclinical data showing that the cytotoxicity of single agent rucaparib was time dependent but in vivo experiments failed to demonstrate any measurable effect on tumor growth
Summary
The Ewing sarcoma family of tumors (ESFT) is the second most common malignant bone or soft tissue tumor in childhood and adolescence, accounting for approximately 1.5% of all pediatric cancers. Significant advances have been made over the past decades with 5-year event-free survival (EFS) rates for patients with localized disease increasing up to 70% [2, 3]. The DNA-dependent protein kinase (DNA-PK) is a central component of NHEJ [7, 8], and a highly potent and specific inhibitor of DNAPK (NU7441; 2-N-morpholino-8-dibenzothiophenylchromen-4-one) has been used successfully in in vitro and in vivo models to sensitize colon cancer cells and CLL blasts to the effects of DNA-damaging chemo- and/or radiotherapy [9, 10]. DNA-PK and PARP inhibitors sensitize cancer cells to chemo- and radiotherapy. Sensitivity to single agent PARP inhibitors has so far been limited to homologous recombination repair (HRR) deficient tumors, exploiting synthetic lethality
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
