ArticleBMC gastroenterology2025
Identification and validation of a lenvatinib resistance-related prognostic signature in HCC, in which PFKFB4 contributes to tumor progression and lenvatinib resistance.
Article in BMC gastroenterology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Mutant-Selective Binding ofInternational journal of molecular sciences · 2026Article
- Multi-tyrosine kinase inhibitors: exploring immunomodulatory effects on various immune cell types in cancer.Cancer cell international · 2026Review
- Targeting phosphofructokinase in cancer: integrating natural products for metabolic reprogramming and therapeutic innovation.Frontiers in pharmacology · 2026Review
- A bibliometric study on microenvironment-mediated drug resistance in interventional liver cancer treatment.Discover oncology · 2025Article
- Aberrant activation of the PI3K/AKT/HIF‑1α pathway promotes glycolysis and lenvatinib resistance in liver cancer.Molecular medicine reports · 2025Article
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Authors and funding
10 authors.
Funding
Abstract
backgroundDrug resistance reflects the evolution of tumors and represents the leading factor behind recurrence and death. Lenvatinib is the first-line therapy for hepatocellular carcinoma (HCC), but its effectiveness is limited by rapid development of resistance. Therefore, we aimed to identify lenvatinib resistance-related genes and assess their influence on prognosis and treatment response in HCC.
methodsThe GSE186191 dataset served as the discovery cohort to identify lenvatinib resistance-related genes. A Venn diagram analysis delineated the intersection between lenvatinib resistance-related genes and prognostic-associated genes derived from The Cancer Genome Atlas (TCGA) database. The LASSO Cox regression model was implemented to construct a multigene signature in the TCGA cohort. A nomogram was built by integrating the TNM stage and our prognostic model. The gene signature and nomogram were further validated using HCC patients from the International Cancer Genome Consortium (ICGC) cohort. Mutation signatures, therapeutic response, functional enrichment, and immune profile analyses were performed in the two groups. Two lenvatinib-resistant (LR) HCC cells were established using a concentration gradient increment method. PFKFB4 expression was detected via qRT-PCR and western blot assay. The CCK-8 assay and flow cytometry were utilized to evaluate the proliferation and apoptosis of LR cells under different interventions.
resultsWe developed a lenvatinib resistance-related gene signature (ALPK3, SLC2A2, CTSV, and PFKFB4), and demonstrated that's a precise, independent, and specific prognostic model for HCC patients. High-risk patients were characterized by a predisposition to TP53 mutations, aggressive tumor features, and treatment resistance. The risk score was significantly associated with immune cell infiltration, immune checkpoint expression, angiogenesis, and tumor stemness. PFKFB4 was overexpressed in LR cells, and its knockdown significantly enhances the antiproliferative and pro-apoptotic effects of lenvatinib on resistant cells.
conclusionsThe lenvatinib resistance-related prognostic signature exhibits strong predictive power for prognosis in HCC patients and may serve as an effective tool for guiding treatment decisions. PFKFB4 promotes tumor progression and lenvatinib resistance, highlighting its potential as a novel therapeutic target for HCC. CLINICAL TRIAL NUMBER: Not applicable.
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