ArticleMolecular cancer2022
Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression.
Article in Molecular cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers, 1 of them a synthesis that pooled it.
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Who cites it
100 citing papers in PubMed, 1 synthesis or guideline pooled it, 135 citations in OpenAlex.
- Statin shapes inflamed tumor microenvironment and enhances immune checkpoint blockade in non-small cell lung cancer.JCI insight · 2022Pooled it
- DHCR24Oncogene · 2026Article
- Sterol regulatory element‑binding proteins: Master regulators of lipid metabolic reprogramming in cancer and emerging therapeutic targets (Review).Oncology reports · 2026Review
- Early radiotherapy delays acquired gefitinib resistance in EGFR-mutant NSCLC by suppressing c-FOS-associated survival signaling.Respiratory research · 2026Article
- Opportunities and challenges in the development of evolving EGFR inhibitors to overcome EGFR TKIs resistance.Acta pharmacologica Sinica · 2026Review
- Lipid Metabolism, Lipogenesis, and Resistance to Third Generation EGFR-TKIs.Journal of clinical laboratory analysis · 2026Review
- Metabolic activation of LDHA by ERRα represses inflammasome-dependent pyroptosis and promotes ovarian cancer chemoresistance.Cell death & disease · 2026Article
- Cholesterol as a metabolic integrator of oncogenic signaling, immune evasion, and therapy resistance.Apoptosis : an international journal on programmed cell death · 2026Review
- Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.Cellular & molecular immunology · 2026Review
- Tissue-specific fibroblast lipid cues impose the rate of epithelial cancer invasion.Nature metabolism · 2026Article
- Copy Number Amplification and c-Myc Transcriptional Activation-Mediated RNA-Binding Protein MEX3A Promotes EGFR-TKI Resistance in Non-Small-Cell Lung Cancer.Thoracic cancer · 2026Article
- MTSS1-dependent ubiquitin modifications mediated by FBXO44 remodel the actin cytoskeleton to promote gastric cancer progression.Molecular cancer · 2026Article
- Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance.The Journal of clinical investigation · 2026Article
- Improvement of prognosis among patients with lung adenocarcinoma through precision therapy: analysis based on The Cancer Genome Atlas.Translational cancer research · 2026Article
- A novel PAAoptosis-inducing ERRα-targeting compound for combating hematopoietic and solid cancers.Cell death discovery · 2026Article
- Targeting cholesterol-driven immunometabolism in cancer: from molecular circuits to clinical translation.Molecular cancer · 2026Review
- The controversial role of metabolic reprogramming in anti-tumor therapy resistance.Discover oncology · 2026Review
- Declined RTN3 stabilizes DHCR7 to induce cholesterol-dependent tumor progression and MEK inhibitors insensitivity in thyroid cancer.Cell death & disease · 2026Article
- Cholesterol Metabolism-related Characteristics Predict Therapeutic Response and Survival in Esophageal Cancer.Journal of advanced research · 2026Article
- Cholesterol Promotes Lung Adenocarcinoma Brain Metastasis by Stabilizing EGFR Protein to Drive EMT, Metabolic Reprogramming, and Premetastatic Niche Formation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
40 more citing papers are in PubMed but not listed here.
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10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance.
methodsEGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay.
resultsLong-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo.
conclusionsOur study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.
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