ArticleCancer research2022
Inhibition of EGFR Overcomes Acquired Lenvatinib Resistance Driven by STAT3-ABCB1 Signaling in Hepatocellular Carcinoma.
Article in Cancer research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 117 papers.
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Who cites it
117 citing papers in PubMed, 160 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
- Metabolites and cancer metastasis.Oncogene · 2026Review
- Efficacy of lenvatinib combined with sintilimab and transcatheter arterial chemoembolization in conversion therapy for unresectable hepatocellular carcinoma.Pakistan journal of medical sciences · 2026Article
- NEK7-induced phosphorylation of EGFR on serine 1070 drives the acquired lenvatinib resistance in hepatocellular carcinoma.Hepatology (Baltimore, Md.) · 2026Article
- Article
- Development of a sensitive plasma lenvatinib quantification method and validation in thyroid cancer patients.Journal of the Endocrine Society · 2026Article
- Article
- Mutant-Selective Binding ofInternational journal of molecular sciences · 2026Article
- SERPINE2-mediated activation of JAK2/STAT3 facilitates NRF2 nuclear translocation and GCLC transcription to confer ferroptosis resistance and lenvatinib resistance in hepatocellular carcinoma.Journal of experimental & clinical cancer research : CR · 2026Article
- RPRD1A drives lenvatinib resistance in hepatocellular carcinoma via the ITGA5-FAK signaling axis.Molecular biomedicine · 2026Article
- Simvastatin Restores Cisplatin Sensitivity by Suppressing the Caveolin-1-Mediated PI3K/AKT Signaling Pathway in Cisplatin-Resistant Cervical Cancer Cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Protein expression profiling of lenvatinib-resistant liver cancer cells and identify B4GALT4 as a critical drug resistance molecule.Discover oncology · 2026Article
- Tumor Anti-Angiogenesis Therapy and Its Influence on Immune Cell Function in the Tumor Microenvironment.Cancer medicine · 2026Review
- Targeting AKR1C1 overcomes lenvatinib resistance in hepatocellular carcinoma through the STAT3-ABC transporters pathway.Journal of gastrointestinal oncology · 2026Article
- mTOR-driven integrin β4-enriched extracellular vesicles from lenvatinib-resistant hepatocellular carcinoma fuel lung metastasis via fibroblast-niche formation.Signal transduction and targeted therapy · 2026Article
- A Novel Niclosamide Sulfate Prodrug with Enhanced Bioavailability Suppresses Hepatocellular Carcinoma via Inhibition of Multiple Signaling Pathways.bioRxiv : the preprint server for biology · 2026Article
- COLEC12high tumor-associated macrophages orchestrate lenvatinib resistance and cancer stemness in hepatocellular carcinoma via paracrine NRG1-HER2/HER3 signaling.Clinical and molecular hepatology · 2026Article
- Regorafenib and Nifuroxazide exert enhanced suppression of hepatocellular carcinoma by inhibiting STAT3 and immune remodeling.Oncology reports · 2026Article
- ERBB3 blockade sensitizes hepatocellular carcinoma to regorafenib after first-line tyrosine kinase inhibitor resistance by inhibiting HIF1A-ABCB1 signaling.Clinical and molecular hepatology · 2026Article
- Malic enzyme 1 contributes to tumorigenesis and lenvatinib resistance in hepatocellular carcinoma via FSP1-dependent ferroptosis evasion.Cell death & disease · 2026Article
57 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
20 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Lenvatinib is an inhibitor of multiple receptor tyrosine kinases that was recently authorized for first-line treatment of hepatocellular carcinoma (HCC). However, the clinical benefits derived from lenvatinib are limited, highlighting the urgent need to understand mechanisms of resistance. We report here that HCC cells develop resistance to lenvatinib by activating EGFR and stimulating the EGFR-STAT3-ABCB1 axis. Lenvatinib resistance was accompanied by aberrant cholesterol metabolism and lipid raft activation. ABCB1 was activated by EGFR in a lipid raft-dependent manner, which significantly enhanced the exocytosis of lenvatinib to mediate resistance. Furthermore, clinical specimens of HCC showed a correlation between the activation of the EGFR-STAT3-ABCB1 pathway and lenvatinib response. Erlotinib, an EGFR inhibitor that has also been shown to inhibit ABCB1, suppressed lenvatinib exocytosis, and combined treatment with lenvatinib and erlotinib demonstrated a significant synergistic effect on HCC both in vitro and in vivo. Taken together, these findings characterize a mechanism of resistance to a first-line treatment for HCC and offer a practical means to circumvent resistance and treat the disease. SIGNIFICANCE: HCC cells acquire resistance to lenvatinib by activating the EGFR-STAT3-ABCB1 pathway, identifying combined treatment with erlotinib as a strategy to overcome acquired resistance and improve the clinical benefit of lenvatinib.
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