DNAR-03. TARGETING POLY (ADP-RIBOSE) SIGNALING TO INDUCE LETHAL DNA DAMAGE IN IDH MUTANT GLIOMA

Abstract

Abstract Isocitrate dehydrogenase (IDH) 1 or 2 mutant gliomas have unique metabolic characteristics and DNA damage response. Radiotherapy and chemotherapy has been proven to be an effective treatment for IDH mutant gliomas. A key mediator of DNA damage response, Poly(ADP-ribose) (PAR) is regulated by opposing enzymes, poly(ADP-ribose) polymerases (PARPs) that synthesizes PAR through enzymatic polymerization of nicotinamide adenine dinucleotide (NAD), and poly(ADP-ribose) glycohydrolase (PARG) that breaks down and recycles PAR. We recently demonstrated that combining PARG inhibitor (PARGi) and Temozolomide (TMZ) in IDH mutant cells drove an imbalanced sequestration of NAD into PAR, resulting in metabolic lethality through NAD depletion. Here, we sought to characterize the effect of combining PARGi and radiation. Isogenic pairs of IDH1-mutant glioma cells, alongside multiple IDH mutant patient-derived glioma cells, were treated with TMZ, radiation, PARPi, PARGi, and combination thereof. In contrast to PARPi which can have a “trapping” effect, PARGi monotherapy displayed no significant difference between IDH mutant and wild-type isogenic cells. However, we found a substantial augmentation of radiation cytoxicity when combined with PARGi, that was genotype-specific in IDH mutant glioma models, mirroring that seen with PARPi and radiation (Wang et al, Science Advances 2020). Unlike TMZ+PARGi, NAD was not depleted with PARGi and radiation. Conversely, the cytotoxic effect was partially reversed with either PARPi or IDH inhibitor, indicative of a key contribution of PAR mediated DNA damage signaling in the IDH mutant context. Therefore, these results support a model of converging vulnerabilities in IDH mutant cells, with PAR-mediated DNA repair mechanisms independent from NAD metabolism.In summary, this study demonstrates that the combination of PARGi and radiation regulates DNA repair pathways with cytoxicity specific to IDH mutant gliomas. Targeting PAR can potentially be a promising treatment for clinical translation in IDH mutant gliomas, minimizing the radiation effect to surrounding normal cells.