ArticleCell death & disease2022
Genetic alterations of Keap1 confers chemotherapeutic resistance through functional activation of Nrf2 and Notch pathway in head and neck squamous cell carcinoma.
Article in Cell death & disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 33 citations in OpenAlex.
- Article
- Hypoxia and Oxidation Pathway Crosstalk in Head and Neck Squamous Cell Carcinoma.Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · 2026Article
- Article
- Sex-based differences in the NRF2 oxidative stress response: Implications for precision therapeutics.Redox biology · 2026Review
- Unraveling the molecular landscape: an overview on gene expression, epigenetic alterations, and therapeutic challenges in head and neck squamous cell carcinoma.Molecular genetics and genomics : MGG · 2026Review
- Engineering combination nanomedicines to overcome cancer resistance.RSC advances · 2026Review
- Canagliflozin and Brusatol Synergize against LKB1-KEAP1 Co-Mutant NSCLC through AKT Suppression.International journal of biological sciences · 2026Article
- Cysteine Metabolism in the Control of Oxidative Stress in Cancer, Focusing on Carbon and Sulfur Metabolism.Advances in experimental medicine and biology · 2026Review
- Synthetic Oleanane Triterpenoids Reduce Tumor Growth and Promote an Anti-Tumor Immune Response Independent of CancerAntioxidants (Basel, Switzerland) · 2025Article
- Mechanisms of Bisphenol A exposure on oral squamous cell carcinoma: a multidimensional network analysis.BMC pharmacology & toxicology · 2025Article
- Immunohistochemical analysis of p53 and LKB1 as predictive biomarkers of immune checkpoint inhibitor response in non-small cell lung cancer.Translational lung cancer research · 2025Article
- A long noncoding RNA-based serum signature predicts ado-trastuzumab emtansine (T-DM1) treatment benefit in HER2+ metastatic breast cancer patients: a multicenter cohort study.Cell death discovery · 2025Article
- Tumour- and Non-Tumour-Associated Factors That Modulate Response to PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer.Cancers · 2025Review
- Genetic Variants in Oxidative Stress-Related Genes and Their Impact on Prognosis and Treatment Response in Chronic Myeloid Leukemia Patients.International journal of molecular sciences · 2025Article
- Article
- Article
- Prediction of Cervical Cancer Progression Leveraging HPV16 Integration-Related Genes.International journal of women's health · 2025Article
- Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants.Molecular cell · 2024Article
- Multi-omics comprehensive analyses of programmed cell death patterns to regulate the immune characteristics of head and neck squamous cell carcinoma.Translational oncology · 2024Article
- Next-Cell Hypothesis: Mechanism of Obesity-Associated Carcinogenesis.Advances in experimental medicine and biology · 2024Review
Corrections and comments
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Authors and funding
10 authors at 6 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Keap1 mutations regulate Nrf2 activity and lead to chemoresistance in cancers. Yet the underlying molecular mechanisms of chemoresistance are poorly explored. By focusing and genotyping head and neck squamous cell carcinoma (HNSCC) that had available pathologic and clinical data, we provide evidence that Keap1 displays frequent alterations (17%) in HNSCC. Functional loss of Keap1 results in significant activation of Nrf2 and promotes cancer cell growth, proliferation, and elevated cancer stem cell (CSCs) self-renewal efficiency and resistance to oxidative stress. Furthermore, decreased Keap1 activity in these cells increased nuclear accumulation of Nrf2 and activation of the Notch pathway, causing enhanced transcriptional alterations of antioxidants, xenobiotic metabolism enzymes, and resistance to chemotherapeutic treatment. Limiting the Nrf2 activity by either Keap1 complementation or by Nrf2 silencing increased the sensitivity to chemotherapy in Keap1-mutated cells and repressed the CSC self-renewal activity. Our findings suggest that Keap1 mutations define a distinct disease phenotype and the Keap1-Nrf2 pathway is one of the leading molecular mechanisms for clinical chemotherapeutic resistance. Targeting this pathway may provide a potential and attractive personalized treatment strategy for overcoming chemotherapeutic resistance conferred by Keap1 mutations.
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