Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-like Cells

Glioblastoma (GBM) may be a fatal primary brain tumour characterised by treatment resistance and inevitable tumor repetition, each of that area unit driven by a population of GBM cancer stem–like cells (GSC) with tumorigenic and self-renewal properties. Despite having broad implications for understanding GSC composition, the determinants of upregulated DNA-damage response (DDR) and resultant radiation resistance in GSC area unit unknown and represent a big barrier to developing effective GBM treatments. during this study, we tend to show that organic DDR activation and radiation resistance area unit driven by high levels of deoxyribonucleic acid replication stress (RS). CD133+ GSC exhibited reduced DNA replication velocity and a higher frequency of stalled replication forks than CD133− non-GSC in vitro; immunofluorescence studies confirmed these observations in a panel of orthotopic xenografts and human GBM specimens. Exposure of non-GSC to low-level exogenous RS generated radiation resistance in vitro, confirming RS as a completely unique determinant of radiation resistance in neoplasm cells. GSC exhibited deoxyribonucleic acid double-strand breaks, that colocalized with “replication factories” and RNA: deoxyribonucleic acid hybrids. GSC additionally incontestible redoubled expression of long neural genes (>1 Mbp) containing common fragile sites, supporting the hypothesis that replication/transcription collisions area unit the possible reason for RS in GSC. Targeting RS by combined inhibition of ATR and PARP (CAiPi) provided GSC-specific toxicity and complete cancellation of GSC radiation resistance in vitro. These knowledge establish RS as a cancer stem cell–specific target with important clinical potential.

Reference

Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-like Cells

Ross D. CarruthersShafiq U. AhmedShaliny RamachandranKaren StrathdeeKathreena M. KurianAnn HedleyNatividad Gomez-RomanGabriela KalnaMathew NeilsonLesley GilmourKatrina H. StevensonEster M. Hammond and Anthony J. Chalmers [Link]