ArticleScientific reports2022
EGFR inhibition reverses resistance to lenvatinib in hepatocellular carcinoma cells.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 56 citations in OpenAlex.
- Efficacy and safety of lenvatinib plus gefitinib in lenvatinib-resistant hepatocellular carcinomas: a prospective, single-arm exploratory trial.Signal transduction and targeted therapy · 2024Trial
- Elucidating the PTK2-Targeted Anti-Hepatocellular Carcinoma Effects ofCurrent issues in molecular biology · 2026Article
- Targeting DDOST improves the efficacy of lenvatinib and immunotherapy in hepatocellular carcinoma.Experimental & molecular medicine · 2025Article
- Aberrant activation of the PI3K/AKT/HIF‑1α pathway promotes glycolysis and lenvatinib resistance in liver cancer.Molecular medicine reports · 2025Article
- Novel combination therapy with phenformin enhances the effects of lenvatinib in hepatocellular carcinoma via AMPK-mediated PDGFRβ degradation.Cancer cell international · 2025Article
- Oligomeric Proanthocyanidins Reverse Lenvatinib Resistance in Hepatocellular Carcinoma Through ITGA3-Mediated Pathway.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Bile acid metabolism and hepatocellular carcinoma: mechanisms of drug resistance and intervention strategies.Precision clinical medicine · 2025Review
- Ozone Exposure Induces Prediabetic Symptoms Through Hepatic Glycogen Metabolism and Insulin Resistance.Toxics · 2025Article
- Inhibition of the Caveolin-1 pathway promotes apoptosis and overcomes pan-tyrosine kinase inhibitor resistance in hepatocellular carcinoma.Cell death & disease · 2025Article
- An aptamer-conjugated mesoporous polydopamine formulation for synergistic targeted and photothermal therapy of hepatocellular carcinoma.International journal of pharmaceutics: X · 2025Article
- Hepatocellular carcinoma: signaling pathways and therapeutic advances.Signal transduction and targeted therapy · 2025Review
- CircUCK2(2,3) promotes cancer progression and enhances synergistic cytotoxicity of lenvatinib with EGFR inhibitors via activating CNIH4-TGFα-EGFR signaling.Cellular & molecular biology letters · 2025Article
- Molecular profiling of circulating tumor cells guides effective EGFR inhibitor treatment in advanced hepatocellular carcinoma: a case report.Frontiers in oncology · 2025Article
- Identification of Key Genes and Pathways in Lenvatinib-resistant Hepatocellular Carcinoma using Bioinformatic Analysis and Experimental Validation.Current medicinal chemistry · 2025Article
- Lenvatinib and immune-checkpoint inhibitors in hepatocellular carcinoma: mechanistic insights, clinical efficacy, and future perspectives.Journal of hematology & oncology · 2024Review
- Establishment and characterization of mouse metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma organoids.Scientific reports · 2024Article
- Article
- Lenvatinib in combination with transarterial chemoembolization vs. sorafenib in combination with transarterial chemoembolization for unresectable hepatocellular carcinoma: A network meta‑analysis.Oncology letters · 2024Article
- Promoting reactive oxygen species accumulation to overcome tyrosine kinase inhibitor resistance in cancer.Cancer cell international · 2024Review
- Mechanisms and therapeutic targets of ErbB family receptors in hepatocellular carcinoma: a narrative review.Translational cancer research · 2024Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Lenvatinib is approved as a first-line treatment for unresectable HCC. The therapeutic duration of lenvatinib is limited by resistance, but the underlying mechanism is unclear. To establish lenvatinib-resistant cells, Hep3B cells were initially treated with 3 µM lenvatinib. The concentration was gradually increased by 1 µM or 0.5 µM per week and it reached to 7.5 µM 2 months after the initial exposure to lenvatinib. The biological characteristics of these cells were analyzed by ERK activation in the MAPK signaling pathway and a human phospho-receptor tyrosine kinase (RTK) antibody array. Factors possibly related to lenvatinib resistance were analyzed using inhibitors, and cell proliferation was analyzed. We established lenvatinib-resistant HCC cells (LR cells) by long-term exposure to lenvatinib. Lenvatinib reduced ERK activation in the parent cells, but not in the LR cells. RTK array analysis showed that the activities of EGFR and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) were significantly increased in LR cells, whereas the activities of other RTKs were unchanged. Erlotinib, a widely used EGFR inhibitor, downregulated ERK activation in LR cells. The proliferation of LR cells will also be affected when lenvatinib is combined with erlotinib to treat LR cells. In contrast, inhibition of IGFR/INSR did not affect ERK activation or cell proliferation. Scavenging of reactive oxygen species (ROS) ameliorated the enhanced EGFR activation in LR cells. Lenvatinib resistance was induced by enhanced EGFR activation, possibly via ROS accumulation, in lenvatinib- resistant cells. These findings may enable the development of lenvatinib combination therapies for HCC.
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