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