Abstract 5429: Targeting Nrf2 anti-oxidative pathway as a novel strategy to suppress IDH1-mutated cancer

Abstract

Abstract Background: Reactive oxygen species are recently recognized as a second messenger that affects many aspects in cell biology. In cancer cells, ROS has been proof closely related to metabolic reprogramming, tumor proliferation, progression and metastasis. In tumors with isocitrate dehydrogenase (IDH) mutations, the neomorphic enzyme results in unusual accumulation of ROS in cancer cells, suggesting distinctive vulnerabilities may be established in these types of cancer. However, the biologic function of ROS in IDH1-mutated cancers remains elusive. Methods: In this study, we explored the ROS homeostasis in IDH1 mutated glioma. We investigated the correlation between ROS scavenging genes and overall survival in 530 IDH1-mutated glioma cases. Mechanistically, we focused on nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway and seek for novel therapeutic strategy by targeting ROS burden in cancer cells. We further investigated the therapeutic value of Nrf2 inhibitor, Brusatol, in IDH1 mutated cancer in vitro and in vivo. Results: We found IDH1 mutation leads to substantial reprogramming in ROS homeostasis, highlighted with prompted ROS generation and detoxification. Stronger expression of ROS scavenging gene predicts drug resistance and poor disease outcome. Enhanced Nrf2-associated scavenging pathway was found essential to maintain reasonable intracellular ROS level during cancer progression. Targeting Nrf2 scavenging pathway not only led to ROS overload, DNA/protein oxidative damage, but also reduced tumor cell proliferation and xenograft growth in vivo. Conclusions: IDH1 mutant glioma highly depend on Nrf2 scavenging pathway to maintain ROS homeostasis. Targeting ROS scavenging might be a novel approach to treat gliomas with IDH1 mutation. Citation Format: Yang Liu. Targeting Nrf2 anti-oxidative pathway as a novel strategy to suppress IDH1-mutated cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5429.