Oxysophocarpine suppresses FGFR1-overexpressed hepatocellular carcinoma growth and sensitizes the therapeutic effect of lenvatinib

Hepatocellular carcinoma (HCC) is an aggressive solid tumor with restricted therapeutics. Lenvatinib is the second approved frontline drug for advanced HCC, however lenvatinib-resistant cases have been reported in clinical. Overexpression of fibroblast growth factor receptor (FGFR1) has been found to be associated with advanced HCC. This study was aimed to investigate the relationship between FGFR1 overexpression and lenvatinib resistance, and explore the potential candidate that can sensitize lenvatinib against FGFR1-overexpressed HCC. Development of FGFR1 overexpression was accomplished in Hep3B and HepG2 cell lines by pCDH-FGFR1 lentiviral vector. In vitro, cell proliferation, colony formation, cell migration and cell apoptosis assays were used to explore the effect of lenvatinib and Oxysophocarpine. In vivo, BALB/c nude mice were burdened with subcutaneous FGFR1-overexpressed Hep3B tumor to assess the therapeutic effect of lenvatinib and Oxysophocarpine. qRT-PCR and western blotting were further used to identify the underlying mechanism. Here, we revealed that overexpressed FGFR1 and its downstream AKT/mTOR and ERK signaling activation could induce lenvatinib resistance in HCC. In vivo and in vitro results showed Oxysophocarpine inhibited the proliferation and induced the apoptosis of FGFR1-overexpressed HCC cells. Oxysophocarpine could further sensitize FGFR1-overexpressed HCC cells to lenvatinib treatment. Mechanism studies revealed that Oxysophocarpine downregulated FGFR1 expression along with downstream AKT/mTOR and ERK signaling to sensitize lenvatinib against FGFR1-overexpressed HCC. These data collectively provided evidence that FGFR1 overexpression could be a potential cause of lenvatinib resistance and Oxysophocarpine could be an ideal combined therapy with lenvatinib in HCC treatment.