Evaluating the Effect of Lenvatinib on Sorafenib-Resistant Hepatocellular Carcinoma Cells

Background/Objective Hepatocellular carcinoma (HCC) is the most common primary liver cancer, with an increasing incidence over the past few decades in various populations; it is one of the major causes of cancer-related deaths worldwide. For a long time, sorafenib has been used as first-line systemic therapy for advanced HCC, and resistance to sorafenib remains a significant issue. A clinical trial showed that the median survival time of lenvatinib was not inferior to that of sorafenib. To determine the effect of lenvatinib in sorafenib-resistant HCC, sorafenib-resistant cell lines were established and experiments were performed.
Methods Two human HCC cell lines, Huh-7 and Hep-3B, were used to establish sorafenib resistance and analyze the effect of lenvatinib on cell proliferation, cell cycle, apoptosis, invasion, and the regulation of microRNAs.
Results Lenvatinib suppressed sorafenib-resistant HCC cell proliferation mainly by inducing G1 cell cycle arrest through ERK signaling. Hep-3B sorafenib-resistant cells showed partial cross-resistance to lenvatinib, possibly due to the contribution of poor autophagic responsiveness. Overall, the findings suggest that the underlying mechanism of lenvatinib in overcoming sorafenib resistance in HCC involves FGFR4-ERK signaling.
Conclusion Lenvatinib may be a suitable second-line therapy for unresectable HCC patients who have developed sorafenib resistance and express FGFR4.