Targeting Replication Stress for Glioma Stem Cell Specific Cytotoxicity

Abstract AIMS Glioma stem cells (GSC) show high levels of DNA replication stress and exhibit abnormal S phase in comparison to differentiated, non GSC tumour cells. We investigated the phenotypes mechanism specific cytotoxicity following response inhibition with combined ATR/PARP (CAiPi). METHOD Paired enriched (‘GSC’) deplete differentiated (‘bulk’) populations were cultured from resected GBM specimens maintained neurobasal media growth factors or serum containing respectively. Cell viability, neurosphere clonogenic assays used assess whilst was interrogated utilising immunofluorescent repair foci, flow cytometry fibre assay. CAiPi consisted VE821 (ATRi) Olaparib (PARPi). RESULTS reduced rates alterations cell cycle profile demonstrate extreme sensitivity CAiPi. resulted significantly elevated 53BP1 nuclear bodies indicating genomic under- replication, however did not preferentially reduce fork speed compared non-GSC. Analysis structures revealed an increase new origin firing dependent upon PARP trapping. by roscovitine induced firing, suggesting important role dysregulated response. is also potently radiosensitising CONCLUSION Taken together these data suggest that are vulnerable dysregulation which results under-replication their genome reliance G1 resolution damage. propose attractive therapeutic strategy for translation clinic.