Hepatitis B Virus-Induced Resistance to Sorafenib and Lenvatinib in Hepatocellular Carcinoma Cells: Implications for Cell Viability and Signaling Pathways.

Simple Summary: In real-life applications, lenvatinib has been found to have a better tumor response than sorafenib in patients with HBV-related HCC, showing that treatment with lenvatinib may be useful in individuals with HBV infections. However, in this study, we show that HBV confers resistance to lenvatinib at an even deeper level than its resistance to sorafenib. It is highly likely that the mechanisms of resistance to these two medications are distinct. Our findings may explain why lenvatinib and sorafenib have had equal effects on overall survival and progression-free survival in patients with HBV-related HCC, despite the apparent potential benefit of sorafenib. However, additional research is required to identify the processes that drive this resistance and to develop more effective therapies for HBV-associated HCC. These findings highlight the need for tailored therapeutic strategies to overcome HBV-induced resistance in HCC treatment. Background/Objectives: Sorafenib and lenvatinib are tyrosine kinase inhibitors used in hepatocellular carcinoma (HCC) treatment. This study investigates how hepatitis B virus (HBV) infection affects their efficacy in HepG2 hepatoma cells. Methods: HepG2 and HBV-infected HepG2/2215 cells were treated with varying concentrations of both drugs. The cell viability, cell cycle gene expression, cycle progression, and phosphorylation levels of ERK and AKT were analyzed. Results: The HBV-infected cells showed significant alterations in their cell cycle gene expressions, with an 80-fold increase in CCND2 expression and a higher proportion of cells in the G2/M phase, indicating enhanced proliferation. While both drugs decreased HepG2 cell viability in a concentration-dependent manner, HBV infection conferred resistance, as evidenced by the increased viable cells in the HepG2/2215 cultures. Sorafenib and lenvatinib decreased key cyclin and cyclin-dependent kinase expressions in uninfected cells, with less effect on the HBV-infected cells. Both drugs lowered the pERK and pAKT levels in the HepG2 cells. In the HBV-infected cells, sorafenib reduced the pERK and pAKT levels to a lesser extent. However, treatment with lenvatinib elevated the levels of pERK and pAKT. Conclusions: In conclusion, HBV infection increases resistance to both sorafenib and lenvatinib in hepatoma cells by influencing the cell cycle regulatory genes and critical signaling pathways. However, the resistance mechanisms likely differ between the two medications. [ABSTRACT FROM AUTHOR]