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Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks

Ke Xu1, Jie Ma2, Sean R R Hall3

  • 1Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China.

Theranostics
|January 12, 2023
PubMed

Insights

The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is frequently altered in non-small cell lung cancer (NSCLC). Aberrant KEAP1/NRF2 signaling drives metabolic and immune changes, impacting treatment resistance and cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway regulates cellular defense against oxidative stress and xenobiotics.
  • Aberrant KEAP1/NRF2 pathway activation is common in non-small cell lung cancer (NSCLC) and influences cancer initiation and progression.
  • Hyperactivated NRF2 signaling is increasingly linked to metabolic reprogramming, immune evasion, and treatment resistance in cancer.

Purpose of the Study:

  • To detail the metabolic and immune adaptations conferred by KEAP1-NRF2 aberration in NSCLC.
  • To compare KEAP1-NRF2 pathway dysregulation in major NSCLC subtypes.
  • To provide mechanistic insights into immunotherapy resistance and explore novel therapeutic strategies for NSCLC.

Main Methods:

  • Literature review and discussion of KEAP1-NRF2 pathway roles in NSCLC.
  • Comparative analysis of KEAP1-NRF2 pathway alterations across NSCLC subtypes.
  • Bioinformatic analysis of public datasets to identify NRF2 pathway interactors.

Main Results:

  • KEAP1-NRF2 aberration confers specific metabolic and immune fitness to NSCLC cells, contributing to aggressiveness and treatment resistance.
  • Distinct KEAP1-NRF2 pathway dysregulation patterns exist between major NSCLC histo-subtypes.
  • Bioinformatic analysis revealed novel NRF2 pathway partners and effectors in NRF2-dependent NSCLC.

Conclusions:

  • KEAP1-NRF2 pathway alterations are critical drivers of NSCLC aggressiveness, metabolic adaptation, and immune evasion.
  • Understanding subtype-specific KEAP1-NRF2 pathway dysregulation is crucial for developing effective therapeutic strategies.
  • Targeting NRF2-dependent pathways and their interactors offers potential for treating resistant NSCLC.
Keywords:
KEAP1-NRF2 signalingbioinformaticsmetabolic reprogrammingnon-small cell lung cancertherapeutic vulnerabilitiestumor immune microenvironment

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