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bioRxiv · 10.64898/2026.08.08.743634

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

Kitagawa, Y.·Nasser, A.·Kobayashi, A.·Wetzel, E.·Melamed, L.·Chang, C.-C.·Miller, J.·Wakimoto, H.·Cahill, D.
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Abstract

Mutations in isocitrate dehydrogenase 1 (IDH1) drive the early stages of gliomagenesis while simultaneously imposing replication stress that creates targetable vulnerabilities. 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. Metabolic repletion of NAD+ fails to rescue this effect, indicating that the vulnerability cannot be explained solely by NAD+ depletion. Instead, PARG inhibition profoundly alters replication fork progression and S-phase kinetics 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. Importantly, pharmacologic inhibition of DNA-PKcs with AZD7648 during irradiation disrupts fork-associated repair signaling and markedly enhances cytotoxicity in IDH1-mutant glioma models. Together, these findings identify a PAR-dependent replication fork vulnerability that can be therapeutically exploited to selectively enhance radiosensitivity in IDH1-mutant gliomas. Statement of significanceIDH-mutant gliomas harbor intrinsic replication stress yet lack targeted radiosensitization strategies. We identify a PAR-dependent replication fork vulnerability in which disruption amplifies radiation cytotoxicity by deregulating S-phase fork signaling. Pharmacologic DNA-PKcs inhibition exploits this dependency, providing a genotype-selective approach to enhance radiotherapy in IDH-mutant glioma.

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Kitagawa, Y., Nasser, A., Kobayashi, A., Wetzel, E., Melamed, L., Chang, C.-C., Miller, J., Wakimoto, H., Cahill, D.. 2026-08-10. Augmenting Radiation Sensitivity by Targeting PAR-Dependent Replication Fork Vulnerability in IDH-Mutant Glioma. https://doi.org/10.64898/2026.08.08.743634

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