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The KEAP1-NRF2 System and Esophageal Cancer

Wataru Hirose1,2, Hiroyuki Oshikiri1,2, Keiko Taguchi1,3,4

  • 1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-Machi, Aoba, Sendai 980-8575, Japan.

Cancers
|October 14, 2022
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (NRF2) pathway alterations drive esophageal squamous cell carcinoma (ESCC) malignancy and treatment resistance. Targeting the KEAP1-NRF2 system offers new therapeutic strategies for NRF2-addicted ESCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of cytoprotective genes.
  • Kelch-like ECH-associated protein 1 (KEAP1) typically controls NRF2 stability via ubiquitination and degradation.
  • Genetic alterations in the KEAP1-NRF2 pathway are prevalent in esophageal squamous cell carcinoma (ESCC), leading to NRF2 activation.

Purpose of the Study:

  • To review the current understanding of the KEAP1-NRF2 system in esophageal cancer.
  • To explore the role of NRF2 activation in ESCC pathogenesis, malignancy, and treatment resistance.
  • To propose therapeutic strategies for NRF2-addicted ESCC.

Main Methods:

  • Literature review of studies on the KEAP1-NRF2 pathway in esophageal cancer.
  • Analysis of genetic alterations and their impact on NRF2 activity in ESCC.
  • Examination of cell competition dynamics in NRF2-activated esophageal tissues.

Main Results:

  • NRF2 activation due to KEAP1-NRF2 system alterations contributes to ESCC malignancy.
  • NRF2-addicted ESCC exhibits resistance to chemoradiotherapy.
  • Recent findings clarify the role of cell competition in NRF2-driven ESCC pathogenesis.

Conclusions:

  • Targeting the KEAP1-NRF2 system is a critical and urgent need for ESCC treatment.
  • Efficient clinical screening for NRF2-addicted ESCC patients is essential.
  • Therapeutic strategies include NRF2 inhibitors, synthetic lethal drugs, and host defense system inducers.
Keywords:
ESCCKEAP1NRF2cell competitionesophageal canceresophagus

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