Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer
Open accessAbstract
BACKGROUND: Nuclear factor erythroid-2 related factor 2 (NRF2) is a redox-sensitive transcription factor that positively regulates the expression of genes encoding antioxidants, xenobiotic detoxification enzymes, and drug efflux pumps, and confers cytoprotection against oxidative stress and xenobiotics in normal cells. Kelch-like ECH-associated protein 1 (KEAP1) negatively regulates NRF2 activity by targeting it to proteasomal degradation. Increased expression of cellular antioxidants and xenobiotic detoxification enzymes has been implicated in resistance of tumor cells against chemotherapeutic drugs. METHODS AND FINDINGS: Here we report a systematic analysis of the KEAP1 genomic locus in lung cancer patients and cell lines that revealed deletion, insertion, and missense mutations in functionally important domains of KEAP1 and a very high percentage of loss of heterozygosity at 19p13.2, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event. Sequencing of KEAP1 in 12 cell lines and 54 non-small-cell lung cancer (NSCLC) samples revealed somatic mutations in KEAP1 in a total of six cell lines and ten tumors at a frequency of 50% and 19%, respectively. All the mutations were within highly conserved amino acid residues located in the Kelch or intervening region domain of the KEAP1 protein, suggesting that these mutations would likely abolish KEAP1 repressor activity. Evaluation of loss of heterozygosity at 19p13.2 revealed allelic losses in 61% of the NSCLC cell lines and 41% of the tumor samples. Decreased KEAP1 activity in cancer cells induced greater nuclear accumulation of NRF2, causing enhanced transcriptional induction of antioxidants, xenobiotic metabolism enzymes, and drug efflux pumps. CONCLUSIONS: This is the first study to our knowledge to demonstrate that biallelic inactivation of KEAP1 is a frequent genetic alteration in NSCLC. Loss of KEAP1 function leading to constitutive activation of NRF2-mediated gene expression in cancer suggests that tumor cells manipulate the NRF2 pathway for their survival against chemotherapeutic agents.
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Mutations to NRF2 and its regulator KEAP1 have been found in cancer cells, supporting the supposition that antioxidant genes are pivotal in tumor progression.
“In this regard, mutations to NRF2 and its regulator KEAP1 have been found in cancer cells, supporting the supposition that antioxidant genes are pivotal in tumor progression59–62.”
From ROS in cancer therapy: the bright side of the moon (2020) · cites this paper as [60]
The Discussion (page not available in our copy) reports KEAP1 mutations in non-small-cell lung tumors and links loss of functional KEAP1 to increased NRF2 activity and expression of antioxidant genes, which may favor malignant progression. The paper reports activation of NRF2, not mutations to NRF2, so it does not support that part of the claim. (LLM, conf=0.89)
Experimental — accuracy not yet measuredSome somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance.
“Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, thereby leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance (e.g., chemoresistance) (Figure 8) [161,162,163,164,165,166,167,168,169,170,171].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [164]
Most of these cancers' aberrant Nrf2 expression and poor prognosis have been attributed to loss-of-function mutations in KEAP1 and/or gain-of-function mutations in NFE2L2.
“most of which have been attributed to loss-of-function mutations in the KEAP1 gene and/or gain-of-function mutations in the NFE2L2 gene encoding Nrf2 [162,163,164,166,167].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [164]
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- Authors
- Singh, A., Misra, V., Thimmulappa, R. K., Lee, H., Ames, S., Hoque, M. O., Herman, J. G., Baylin, S. B., Sidransky, D., Gabrielson, E., Brock, M. V., & Biswal, S.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Biswal, Shyam
- ORCID
- Venue
- PLoS Medicine
- Publisher
- Public Library of Science (PLoS)
- Published
- 2006-10-03
- Volume
- 3
- Issue
- 10
- Pages
- e420
- ISSN
- 1549-1277 (ISSN-L)
- 1549-1676
- OpenAlex
- W2161446823
- Cited by
- 1,060
- References
- 5
- Citations by year
- 2026: 39 · 2025: 38 · 2024: 34 · 2023: 62 · 2022: 51 · 2021: 59 · 2020: 86 · 2019: 58 · 2018: 56 · 2017: 55 · 2016: 68 · 2015: 72 · 2014: 69 · 2013: 66 · 2012: 63
- FWCI
- 10.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Flight Attendant Medical Research Institute
- Johns Hopkins University
- National Institutes of Health
- Johns Hopkins Bloomberg School of Public Health
- National Heart, Lung, and Blood Institute (R01HL081205, HL 081205)
- National Cancer Institute (P50CA058184)
- National Institute of Environmental Health Sciences (P30-ES-038819)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- Keap1, Nrf2, non-small cell lung cancer, biallelic inactivation, loss of heterozygosity, somatic mutations, antioxidant gene expression, drug efflux pumps, chemoresistance, oxidative stress, Kelch domain
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Adenocarcinoma, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Humans, Lung Neoplasms, Mutation, Gene Expression Regulation, Neoplastic, Carcinoma, Large Cell, Drug Resistance, Neoplasm, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2
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