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The PI3K pathway is a downstream effector of NRF2 activation in the esophagus

Boopathi Subramaniyan1, Yahui Li1, Zhaohui Xiong2

  • 1Surgical Research Lab, Department of Surgery, Cooper University Health Care, Camden, NJ, 08103, USA.

Translational Oncology
|December 4, 2025
PubMed

Insights

Mutations in nuclear factor erythroid 2-related factor 2 (NRF2) activate cancer pathways in esophageal squamous cell carcinoma. Targeting NRF2 and the PI3K pathway shows promise for treating NRF2-mutated ESCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Mutations in nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2) are common in esophageal squamous cell carcinoma (ESCC), leading to NRF2 activation.
  • Activated NRF2 promotes tumor progression and therapeutic resistance, but specific downstream kinases remain largely unidentified.

Purpose of the Study:

  • To identify specific kinases responsive to NRF2 activation in ESCC.
  • To investigate the role of the phosphatidylinositol 3-kinase (PI3K) pathway in NRF2-driven ESCC.
  • To evaluate the therapeutic potential of co-targeting NRF2 and the PI3K pathway.

Main Methods:

  • Protein phosphorylation and kinase activity profiling in NRF2-mutated versus NRF2-null ESCC cells.
  • In vivo studies using genetically engineered mouse models of ESCC.
  • Analysis of human ESCC tissues to correlate NRF2 activation with pathway markers.

Main Results:

  • The PI3K pathway was identified as a key downstream effector of NRF2 activation.
  • NRF2 deficiency sensitized ESCC cells to EGFR, PIK3CA, and AKT inhibitors.
  • Co-treatment with NRF2 and PI3K inhibitors synergistically suppressed tumor growth in vitro and in vivo.
  • NRF2 activation correlated with PI3K pathway activation in human ESCC tissues.

Conclusions:

  • The PI3K pathway is a critical downstream target of NRF2 activation in esophageal cancer.
  • Combined inhibition of NRF2 and the PI3K pathway represents a promising therapeutic strategy for NRF2-mutated ESCC.
Keywords:
Esophageal squamous cell carcinomaEsophagusNRF2PIK3CA

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