Increased c-SRC expression is involved in acquired resistance to lenvatinib in hepatocellular carcinoma

Lenvatinib, a multi-kinase inhibitor, serves a crucial role in the treatment of unresectable hepatocellular carcinoma (HCC). However, >50% of patients receiving lenvatinib therapy experience tumor growth or metastasis within 1 year, highlighting the need to address acquired resistance as a critical clinical challenge. To elucidate the factors associated with acquired resistance to lenvatinib, a lenvatinib-resistant HCC cell line (JHH-7_LR) was established by exposing a lenvatinib-sensitive HCC cell line, JHH-7, to lenvatinib. The changes in protein expression associated with the development of resistance were analyzed using a proteomic approach, detecting 1,321 proteins and significant changes in the expression of 267 proteins. Using Ingenuity Pathway Analysis bioinformatics software, it was revealed that the activity of multiple signaling pathways varied alongside the changes in expression of these proteins, and c-SRC was identified as a protein involved in a number of these signaling pathways, with its activity varying markedly upon the acquisition of resistance. When co-administering dasatinib, a c-SRC inhibitor, the partial restoration of lenvatinib sensitivity in the JHH-7_LR cell line was observed. The present study demonstrated that increased c-SRC expression was partially associated with HCC resistance to lenvatinib, suggesting that c-SRC inhibition could reduce the resistance of HCC to lenvatinib.