LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells

Abstract Background: Due to the reactivation of ERK signaling in sorafenib-resisitant hepatocellular carcinoma (HCC) cells, in this study, the anti-cancer effect of LY3214996 (selective ERK1/2 inhibitor) combined with sorafenib on HCC cells was evaluated. Methods: Phosphorylation of the key kinases in the Ras/Raf/MAPK and PI3K/Akt pathways were detected using Western blot. Cells proliferation, migration, cell cycle and apoptosis were evaluated in Huh7 and Huh7 R cells. Results: LY3214996 significantly reduced phosphorylation levels of the tested kinases of Ras/Raf/MAPK and PI3K/Akt pathways including p-c-Raf, p-P90RSK, p-S6K and p-eIF4EBP1 activated by sorafenib, despite increased p-ERK1/2 levels. It was found that LY3214996 enhanced the anti-proliferation, anti-migration, blocking cell cycle progression and pro-apoptotic effects of sorafenib on Huh7 R cells. Conclusions: The reactivation of ERK1/2 might be highly related to molecular mechanism of acquired drug resistance. LY3214996 combined with sorafenib enhanced anti-tumor effects in HCC. Consequently, combined treatment of LY3214996 and sorafenib provides a second-line therapy for acquired resistant in advanced HCC.