Abstract 875: Targeting Nrf2 driven glutathione de novo synthesis as a novel strategy to suppresses IDH1-mutated glioma

Abstract

Abstract Background: Isocitrate dehydrogenase (IDH) mutation frequently occurs in low grade glioma and secondary glioblastoma, characterizing by the abnormally catalyzation of alpha-ketoglutarate (α-KG) to D-2-hydroxyglutarate (D-2-HG), which induces CpG island methylator phenotype, as well as metabolic reprogramming and high reactive oxygen species (ROS) generation. Our previous data showed that nuclear factor-erythroid 2-related factor 2 (Nrf2) plays a crucial role in maintaining redox homeostasis of IDH1-mutated glioma cells, while the detail mechanism remains elusive. Our recent data showed that glutathione de novo synthesis is governed by Nrf2, which makes great contribution to ROS scavenging in IDH1-mutated tumors and could serve as a potential therapeutic target. Methods: In this study, we explored the important role of glutathione de novo synthetic pathway in maintaining ROS homeostasis by small RNA interference of key enzymes GCLC, GCLM and SLC7A11. We also investigated the correlation between Nrf2 and glutathione de novo synthetic pathway by Chromatin Immunoprecipitation. We further investigated the therapeutic value of Nrf2 inhibitor, Brusatol, in IDH1-mutated cancer both in vitro and in vivo. Results: Our data showed that IDH1 mutation cells exhibit high level steady-state of ROS generation and detoxification. Prolonged Nrf2 activity enhanced transcriptional activity of key enzymes in glutathione de novo synthesis, such as GCLC, GCLM and SLC7A11. Targeting Nrf2 using Brusatol suppressed glutathione synthesis in IDH1-mutated cells, resulted in cytotoxic effect and suppressed xenograft growth in vivo. Conclusions: IDH1-mutated glioma highly depends on Nrf2 activity to maintain ROS homeostasis. Enhanced glutathione de novo synthesis is an important mechanism that governed by Nrf2 and plays critical role in ROS scavenging. Targeting ROS scavenging might be a novel approach to treat gliomas with IDH1 mutation. Citation Format: Yang Liu, Di Yu, Sabrina Cai, Chunzhang Yang. Targeting Nrf2 driven glutathione de novo synthesis as a novel strategy to suppresses IDH1-mutated glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 875.