HIF-1 Signaling Contributes to Lenvatinib Resistance in Patient-Derived HCC Organoids
Resistance to lenvatinib remains an important limitation in the treatment of hepatocellular carcinoma (HCC). In this study, six patient-derived HCC organoid lines were established and classified as lenvatinib-sensitive or lenvatinib-resistant according to their ex vivo drug responses. The organoids retained histological and immunophenotypic features of their matched parental tumors. Lenvatinib-sensitive organoids exhibited more pronounced morphological changes and reduced ATP activity at higher lenvatinib concentrations, whereas ATP activity remained largely unchanged in resistant organoids. Transcriptome sequencing identified 408 upregulated and 269 downregulated genes in lenvatinib-resistant compared with lenvatinib-sensitive organoids, with HIF-1 signaling among the altered pathways. In resistant organoids, lenvatinib increased HIF-1alpha, ANGPT2, and HK3 mRNA expression, whereas comparable changes were not detected in sensitive organoids. KC7F2 reduced the lenvatinib-associated increases in these transcripts and further decreased ATP activity when combined with lenvatinib in resistant organoids. In organoid-derived xenografts, the combination of lenvatinib and KC7F2 resulted in the greatest reduction in tumor growth and lower HIF-1alpha, ANGPT2, and HK3 mRNA expression than lenvatinib alone. These findings indicate that HIF-1 signaling contributes to the lenvatinib-resistant phenotype in patient-derived HCC organoids and that its inhibition may enhance the response to lenvatinib.