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Targeting LEF1-mediated epithelial-mesenchymal transition reverses lenvatinib resistance in hepatocellular carcinoma

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Summary

Acquired resistance is a significant hindrance to clinical application of lenvatinib in unresectable hepatocellular carcinoma (HCC). Further in-depth investigation of resistance mechanisms can help to develop additional therapeutic strategies to overcome or delay resistance. In our study, two lenvatinib-resistant (LR) HCC cell lines were established by treatment with gradient increasing concentration of lenvatinib, named Hep3B-LR and HepG2-LR. Interestingly, continuous lenvatinib treatment reinforced epithelial-mesenchymal transition (EMT), cell migration, and cell invasion. Gene set enrichment analysis (GSEA) enrichment analysis of RNA-sequencing from Hep3B-LR and corresponding parental cells revealed that activation of Wnt signaling pathway was involved in this adaptive process. Active β-catenin and its downstream target lymphoid enhancer binding factor 1 (LEF1) were significantly elevated in LR HCC cells, which promoted lenvatinib resistance through mediating EMT-related genes. Data analysis based on Gene Expression Omnibus (GEO) and the Cancer Genome Atlas Program (TCGA) databases suggests that LEF1, as a key regulator of EMT, was a novel molecular target linked to lenvatinib resistance and poor prognosis in HCC. Using a small-molecule specific inhibitor ICG001 and knocking down LEF1 showed that targeting LEF1 restored the sensitivity of LR HCC cells to lenvatinib. Our results uncover upregulation of LEF1 confers lenvatinib resistance by facilitating EMT, cell migration, and invasion of LR HCC cells, indicating that LEF1 is a novel therapeutic target for overcoming acquired lenvatinib resistance.

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Funding

Our research was supported by the National Natural Science Foundation of China (NO. 81972664) and Natural Science Foundation of Jiangsu Province (No. BK20231419).

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Authors and Affiliations

  1. Department of Medical Genetics and Developmental Biology, School of Medicine, The Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, 87 Dingjiaqiao Road, Nanjing, 210009, Jiangsu, China

    Xinxiu Li, Hongmeng Su, Luyu Zhao & Hong Fan

  2. School of Life Science and Technology, Southeast University, Nanjing, China

    Wenqing Tang, Shihui Shu & Jinghan Sun

Authors
  1. Xinxiu Li
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  2. Hongmeng Su
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  4. Shihui Shu
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  7. Hong Fan
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Contributions

Xinxiu Li carried out the in vitro experiments and drafted the manuscript. Hongmeng Su, Luyu Zhao, and Jinghan Sun implemented bioinformatics analysis. Shihui Shu and Wenqing Tang performed cell culture and revised the manuscript. Hong Fan designed the project. All authors read and approved the final manuscript.

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Correspondence to Hong Fan.

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Li, X., Su, H., Tang, W. et al. Targeting LEF1-mediated epithelial-mesenchymal transition reverses lenvatinib resistance in hepatocellular carcinoma. Invest New Drugs 42, 185–195 (2024). https://doi.org/10.1007/s10637-024-01426-2

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