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NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer

John D Hayes1, Michael McMahon

  • 1Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK. j.d.hayes@dundee.ac.uk

Trends in Biochemical Sciences
|March 27, 2009
PubMed

Insights

Nuclear factor-erythroid 2-related factor 2 (NRF2) regulates cellular defense against stress. Mutations in KEAP1 or NRF2 in lung cancer allow NRF2 activation, potentially leading to drug resistance.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cellular Stress Response

Background:

  • Nuclear factor-erythroid 2-related factor 2 (NRF2) is a transcription factor crucial for cellular adaptation to oxidative and electrophilic stress.
  • NRF2 activity is primarily regulated by Kelch-like ECH-associated protein 1 (KEAP1), which normally represses NRF2.
  • Dysregulation of the NRF2-KEAP1 pathway is implicated in various cancers, including lung cancer.

Purpose of the Study:

  • To investigate the role of somatic mutations in KEAP1 and NRF2 in lung cancer.
  • To understand the molecular mechanisms underlying NRF2 dysregulation in cancer.
  • To explore the potential link between constitutive NRF2 activation and drug resistance in tumors.

Main Methods:

  • Analysis of somatic mutations in KEAP1 and NRF2 in lung cancer patient cohorts.
  • Investigating the impact of these mutations on NRF2 activity and downstream gene expression.
  • Correlating NRF2 pathway alterations with clinical outcomes and drug resistance.

Main Results:

  • Approximately 15% of lung cancer patients exhibit KEAP1 mutations that impair NRF2 repression.
  • Around 10% of lung cancer patients have specific NRF2 mutations ('hot-spots') that enable evasion of KEAP1-mediated inhibition.
  • These mutations lead to constitutive activation of the NRF2 transcription factor.

Conclusions:

  • Somatic mutations in KEAP1 and NRF2 are significant drivers of NRF2 pathway dysregulation in lung cancer.
  • Constitutive NRF2 activation due to these mutations may contribute to therapeutic resistance in tumors.
  • Understanding these regulatory mechanisms offers potential strategies to overcome drug resistance in NRF2-activated cancers.

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