ArticleCell communication and signaling : CCS2020
Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation.
Article in Cell communication and signaling : CCS, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52 citing papers in PubMed, 76 citations in OpenAlex.
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- Kaempferol-based nanocarriers as a potential therapeutic strategy against drug-resistant lung cancer.Cancer cell international · 2026Review
- Context-dependent NRF2 signaling in cancer: mechanisms and precision modulation.Molecular biology reports · 2026Review
- Mangiferin in human disease: Multifaceted mechanisms and applications (Review).International journal of molecular medicine · 2026Review
- NRF2 pathway activation predicts poor prognosis in lung cancer: a cautionary note on antioxidant interventions.GeroScience · 2026Article
- Targeting Lung Cancer Metabolism: Therapeutic Opportunities and Challenges.Advances in experimental medicine and biology · 2026Review
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- The Central Role of NRF2 in Cancer Metabolism and Redox Signaling: Novel Insights into Crosstalk with ER Stress and Therapeutic Modulation.Cell biochemistry and biophysics · 2025Review
- Synthetic Oleanane Triterpenoids Reduce Tumor Growth and Promote an Anti-Tumor Immune Response Independent of CancerAntioxidants (Basel, Switzerland) · 2025Article
- Ferroptosis and cancer: when iron turns against tumors.Cellular and molecular life sciences : CMLS · 2025Review
- Revealing genetic drivers of ovarian cancer and chemoresistance: insights from whole-genome CRISPR-knockout library screens.Cellular oncology (Dordrecht, Netherlands) · 2025Review
- The potential ofJournal of thoracic disease · 2025Article
- Genetic drivers of tumor microenvironment and immunotherapy resistance in non-small cell lung cancer: the role ofJournal for immunotherapy of cancer · 2025Review
- Epigenetic Mechanisms Governing Nrf2 Expression and Its Role in Ferroptosis.Biomedicines · 2025Review
- Double vulnerability of active-NRF2 lung squamous cell carcinoma to NRF2 and TRIM24.Molecular cancer · 2025Article
- Iron overload enhances the susceptibility to cysteine deprivation-induced ferroptosis in non-small cell lung cancer cells.Medical oncology (Northwood, London, England) · 2025Article
- Article
- A histochemical approach to activity-based copper sensing reveals cuproplasia-dependent vulnerabilities in cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeTargeted therapy and immunotherapy have led to dramatic change in the treatment of lung cancer, however, the overall 5-year survival rate of lung cancer patients is still suboptimal. It is important to exploit new potential of molecularly targeted therapies. High-frequency somatic mutations in KEAP1/NRF2 (27.9%) have been identified in lung squamous cell carcinoma. In this research, we explored the role of KEAP1 somatic mutations in the development of LSCC and whether a nuclear factor erythroid 2-related factor 2(NRF2) inhibitor be potential to target lung cancer carrying KEAP1/NRF2 mutations.
methodsLung cancer cell lines A549 and H460 with loss-of-function mutations in KEAP1 stably transfected with wild-type (WT) KEAP1 or somatic mutations in KEAP1 were used to investigate the functions of somatic mutations in KEAP1. Flow cytometry, plate clone formation experiments, and scratch tests were used to examine reactive oxygen species, proliferation, and migration of these cell lines.
resultsThe expression of NRF2 and its target genes increased, and tumor cell proliferation, migration, and tumor growth were accelerated in A549 and H460 cells stably transfected with KEAP1 mutants compared to control cells with a loss-of-function KEAP1 mutation and stably transfected with WT KEAP1 in both in vitro and in vivo studies. The proliferation of A549 cell line trasfected with the R320Q KEAP1 mutant was inhibited more apparent than that of the A549 cell line trasfected with WT KEAP1 after treatment with NRF2 inhibitor ML385.
conclusionSomatic mutations of KEAP1 identified from patients with LSCC likely promote tumorigenesis mediated by activation of the KEAP1/NRF2 antioxidant stress response pathway. NRF2 inhibition with ML385 could inhibit the proliferation of tumor cells with KEAP1 mutation. Video abstract.
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