Protein Kinase B (PKB/AKT) Protects IDH-Mutated Glioma from Ferroptosis via Nrf2

Purpose: Mutations of the isocitrate dehydrogenase (IDH) gene are common genetic mutations in human malignancies. Increasing evidence indicates that IDH mutations play critical roles in malig-nant transformation and progression. However, the therapeutic options for IDH-mutated cancers remain limited. In this study, the investigation of patient cohorts revealed that the PI3K/protein kinase B (AKT) signaling pathways were enhanced in IDH-mutated cancer cells.Experimental Design: In this study, we investigated the gene expression profile in IDH-mutated cells using RNA sequencing after the depletion of AKT. Gene set enrichment analysis (GSEA) and pathway enrichment analysis were used to discover altered molecular pathways due to AKT depletion. We further investigated the therapeutic effect of the AKT inhibitor, ipatasertib (Ipa), combined with temozolomide (TMZ) in cell lines and preclinical animal models. Results: GSEA and pathway enrichment analysis indicated that the PI3K/AKT pathway significantly correlated with Nrf2-guided gene expression and ferroptosis-related pathways. Mechanistically, AKT suppresses the activity of GSK3(3 and stabilizes Nrf2. Moreover, inhibition of AKT activity with Ipa synergizes with the genotoxic agent TMZ, leading to overwhelming ferroptotic cell death in IDH-mutated cancer cells. The preclinical animal model confirmed that combining Ipa and TMZ treatment prolonged survival.Conclusions: Our findings highlighted AKT/Nrf2 pathways as a potential synthetic lethality target for IDH-mutated cancers.