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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
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Protein Kinase B (PKB/AKT) Protects IDH-Mutated Glioma from Ferroptosis via Nrf2

Yang Liu1, Fu-Ju Chou1, Fengchao Lang1

  • 1Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|January 17, 2023
PubMed
Abstract

Insights

Targeting the AKT/Nrf2 pathway with ipatasertib and temozolomide shows promise for treating isocitrate dehydrogenase (IDH)-mutated cancers. This combination therapy induces ferroptosis and improves survival in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Isocitrate dehydrogenase (IDH) gene mutations are prevalent in human cancers, driving malignant transformation and progression.
  • Current therapeutic strategies for IDH-mutated cancers are limited, necessitating novel treatment approaches.
  • Enhanced PI3K/protein kinase B (AKT) signaling pathways are observed in IDH-mutated cancer cells.

Purpose of the Study:

  • To investigate the molecular pathways affected by AKT signaling in IDH-mutated cancer cells.
  • To explore the therapeutic potential of inhibiting the AKT pathway in combination with standard chemotherapy.
  • To identify novel therapeutic targets for IDH-mutated malignancies.

Main Methods:

  • RNA sequencing was employed to analyze gene expression profiles following AKT depletion in IDH-mutated cells.
  • Gene set enrichment analysis (GSEA) and pathway enrichment analysis were utilized to identify altered molecular pathways.
  • The combination therapy of AKT inhibitor ipatasertib (Ipa) and temozolomide (TMZ) was evaluated in cell lines and preclinical animal models.

Main Results:

  • The PI3K/AKT pathway was found to be significantly correlated with Nrf2-guided gene expression and ferroptosis-related pathways.
  • AKT was identified to suppress GSK3β activity, leading to the stabilization of Nrf2.
  • Combination treatment with Ipa and TMZ induced significant ferroptotic cell death in IDH-mutated cancer cells and prolonged survival in animal models.

Conclusions:

  • The AKT/Nrf2 signaling axis represents a potential synthetic lethality target for IDH-mutated cancers.
  • Combined inhibition of AKT and genotoxic therapy offers a promising therapeutic strategy.
  • Targeting the AKT/Nrf2 pathway may overcome limitations in treating IDH-mutated malignancies.

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