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bioRxiv · 10.1101/2020.06.30.180216

Role of PARylation and PTEN Mutation on PARP and PARG Inhibitor Efficacy on Glioblastoma

Hermanowski, H.·Huebert, B.·Aldrighetti, C.·Hurley, J. K.·Quenet, D.
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Abstract

Glioblastoma (GBM) is the most aggressive primary adult brain tumor, with a median survival of approximately 15 months. Despite novel therapeutic approaches, median survival has remained largely unchanged since the standard of care therapy for GBM was established nearly 15 years ago. Phosphatase and tensin homolog (PTEN) is a prognostic biomarker of GBM. PTEN mutation is associated with defects in homologous recombination (HR), making it a candidate for targeted therapy by synthetic lethality (SL). The SL concept has been clinically validated in HR-deficient breast and ovarian cancers upon treatment with poly(ADP-ribose) polymerase (PARP 1) inhibitors (PARPi). This inhibitor, as well as poly(ADP-ribose) glycohydrolase (PARG) inhibitors (PARGi), dysregulate PARylation post-translational modification, which plays a major role in DNA repair and genomic stability. To determine whether PARPi/PARGi promotes SL in GBM, this study investigated the effects of PARPi (veliparib and olaparib) and PARGi in GBM cells with wildtype versus mutant PTEN. Sensitivity to these drugs was analyzed in function of PTEN status. Specifically, PTEN-wildtype cells displayed higher levels of DNA damage after PARPi treatment compared to PTEN-mutant cells. However, focusing on DNA double-strand break (DSB) repair, there was no indication of efficient activation of non-homologous end joining (NHEJ) or homologous recombination (HR). These findings highlight the complex relationship between PARylation and PTEN. Thus, our results do not support the SL between PARP/PARG inhibition and PTEN mutations in GBM cells in absence of other DNA damaging agents.Competing Interest StatementThe authors have declared no competing interest.View Full Text

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Hermanowski, H., Huebert, B., Aldrighetti, C., Hurley, J. K., Quenet, D.. 2020-07-01. Role of PARylation and PTEN Mutation on PARP and PARG Inhibitor Efficacy on Glioblastoma. https://doi.org/10.1101/2020.06.30.180216

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