CSIG-26. PROTEIN KINASE B (PKB/AKT) PROTECTS IDH-MUTATED GLIOMA FROM FERROPTOSIS VIA NRF2

Abstract BACKGROUND Mutations of the isocitrate dehydrogenase (IDH) gene are highly prevalent in WHO II/III glioma. IDH-mutated glioma frequently exhibits strong molecular signatures PI3K/AKT/mTOR signaling, whereas precise roles this oncogenic pathway remain elusive. METHODS In study, we performed unbiased RNA sequencing and set enrichment analysis (GSEA) to investigate relevant pathways governed by Phosphoinositide 3-kinase (PI3K)/AKT cancer cells. The role nuclear factor erythroid 2-related 2 (Nrf2) glutathione de novo synthesis were further analyzed through biochemistry assays. Moreover, AKT disease outcomes was evaluated a preclinical animal model bearing orthoptic intracranial xenograft. RESULTS GSEA indicated that significantly correlated with Nrf2-guided expression ferroptosis-related pathways. Mechanistically, activation compromised phosphorylation Nrf2 at its SDS domain, which is critical post-translational modification determines degradation an E3 ligase β-transducin repeat-containing protein (β-TrCP). Thus, limited proteolysis remarkably enhanced transcriptional activity, enables cytoprotective such as antioxidant, tumor microenvironment remodeling, ferroptosis protection. combination inhibitor ipatasertib genotoxic agent temozolomide resulted potent synthetic lethality cells, highlighted ferroptotic cell death. Further, TMZ regimen improved orthotopic xenograft, prolonged overall survival. CONCLUSION Overall, our findings revealed uncharted mechanism glioma, AKT/Nrf2-guided pathway. Our study also provides evidence for approach IDH mutated cancers.