Ramucirumab and GSK1838705A Enhance the Inhibitory Effects of Low Concentration Sorafenib and Regorafenib Combination on HCC Cell Growth and Motility

Several new multikinase inhibitors have recently been approved for clinical use in the treatment of hepatocellular carcinoma (HCC). While these inhibitors have shown modest improvements in survival, they are associated with significant toxicity. Therefore, there is a critical need for more effective therapies with reduced side effects. This study explored whether combining sorafenib and regorafenib at very low concentrations could maintain efficacy while minimizing clinical toxicity. We assessed cell proliferation using the MTT assay, clonogenic assay, Ki67 staining, and cell cycle analysis, while apoptosis was evaluated through Annexin V staining and western blotting for cleaved Caspase-3 and BID expression. Under these experimental conditions, the combination effectively inhibited cell growth and migration, and induced apoptosis, even in HCC cells with high alpha fetoprotein (AFP) levels, which are typically associated with poor clinical prognosis. Additionally, the combination reduced levels of the two HCC biomarkers, AFP and des-gamma carboxy prothrombin (DCP). Further inhibition of Vascular Endothelial Growth Factor Receptor (VEGFR) or Insulin-like Growth Factor 1 Receptor (IGF1R) enhanced the effects on AFP and DCP levels, as well as inhibiting cell growth and the MAPK and PI3K/Akt signaling pathways. These results suggest that the sorafenib/regorafenib combination may offer a way to enhance therapeutic efficacy while reducing toxicity. Ongoing studies GSK1838705A are further investigating the potential for reduced toxicity with this combination.

Keywords: combination therapy; des-γ-carboxyprothrombin; insulin-like growth factor 1 receptor; multi-kinase inhibitors; synergism; vascular endothelial growth factor receptor; α fetoprotein.