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

• DOI: 10.1158/1078-0432.c.6533045.v1
• Publication Date: 2023-04-01T03:43:14Z
• Authors: Yang Liu; Fu-Ju Chou; Fengchao Lang; Meili Zhang; Hua Song; Wei Zhang; Dionne L. Davis; Nicole J. Briceno; Yang Zhang; Patrick J. Cimino; Kareem A. Zaghloul; Mark R. Gilbert; Terri S. Armstrong; Chunzhang Yang
• Keywords: Isocitrate dehydrogenase; Synthetic Lethality

<div>AbstractPurpose:<p>Mutations of the isocitrate dehydrogenase (<i>IDH</i>) gene are common genetic mutations in human malignancies. Increasing evidence indicates that IDH play critical roles malignant transformation and progression. However, therapeutic options for IDH-mutated cancers remain limited. In this study, investigation patient cohorts revealed PI3K/protein kinase B (AKT) signaling pathways were enhanced cancer cells.</p>Experimental Design:<p>In we investigated expression profile cells using RNA sequencing after depletion AKT. Gene set enrichment analysis (GSEA) pathway used to discover altered molecular due AKT depletion. We further effect inhibitor, ipatasertib (Ipa), combined with temozolomide (TMZ) cell lines preclinical animal models.</p>Results:<p>GSEA indicated PI3K/AKT significantly correlated Nrf2-guided ferroptosis-related pathways. Mechanistically, suppresses activity GSK3β stabilizes Nrf2. Moreover, inhibition Ipa synergizes genotoxic agent TMZ, leading overwhelming ferroptotic death cells. The model confirmed combining TMZ treatment prolonged survival.</p>Conclusions:<p>Our findings highlighted AKT/Nrf2 as a potential synthetic lethality target cancers.</p></div>