Augmenting Radiation Sensitivity by Targeting PAR-Dependent Replication Fork Vulnerability in IDH- Mutant Glioma.

In vitro and in vivo models investigating PARG inhibition in IDH1-mutant glioma cells

“Using both in vitro and in vivo models, we show that inhibition of poly(ADP-ribose) glycohydrolase (PARG) induces a poly(ADP-ribose) (PAR)-dependent augmentation of radiosensitivity in IDH1 -mutant glioma cells.”

IDH1-mutant glioma cells and models

“Using both in vitro and in vivo models, we show that inhibition of poly(ADP-ribose) glycohydrolase (PARG) induces a poly(ADP-ribose) (PAR)-dependent augmentation of radiosensitivity in IDH1 -mutant glioma cells.”

PARG inhibition alters replication fork progression and S-phase kinetics in IDH1-mutant cells

“Instead, PARG inhibition profoundly alters replication fork progression and S-phase kinetics in IDH1 -mutant cells.”

Ionizing radiation preferentially activates DNA-PKcs and XRCC1 in IDH1-mutant cells

“Mechanistically, ionizing radiation preferentially activates replication fork-associated damage response proteins DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and X-ray repair cross-complementing protein 1 (XRCC1) in IDH1 -mutant cells, a response partially reversed by pharmacologic inhibition of mutant IDH1 .”

Pharmacologic inhibition of DNA-PKcs enhances cytotoxicity in IDH1-mutant glioma models during irradiation

“Importantly, pharmacologic inhibition of DNA-PKcs with AZD7648 during irradiation disrupts fork-associated repair signaling and markedly enhances cytotoxicity in IDH1 -mutant glioma models.”