BEZ235 increases sorafenib inhibition of hepatocellular carcinoma cells by suppressing the PI3K/AKT/mTOR pathway

Background: Sorafenib is an oral multi-kinase inhibitor that inhibits hepatocellular carcinoma (HCC) via the Ras/Raf/MAPK pathway. However, sorafenib loses effectiveness because most tumors acquire drug resistance over time. As the PI3K/Akt/mTOR signaling pathway is also activated abnormally in HCC, we evaluated the effect of sorafenib, in combination with a dual PI3K/mTOR Inhibitor, BEZ235, on HCC cell proliferation and survival in vitro.

Materials and methods: Biological phenotypes were analysed in HCC cell lines, parental and sorafenib-resistant HepG2 cells (HepG2 and HepG2^R), treated with sorafenib or BEZ235, alone or in combination. HCC cellular proliferation and Apoptosis were investigated, and perturbations of the Ras/Raf/MAPK and PI3K/Akt/mTOR signaling/survival pathways were evaluated by western blot analysis.

Results: BEZ235 enhanced sorafenib inhibition of cellular proliferation, migration, and promotion of Apoptosis in HepG2 and HepG2^R cells. The combined effects were associated with inhibition of phosphorylation of Akt, mTOR and S6K in the PI3K/Akt/mTOR pathway, whereas the combination of sorafenib and BEZ235 did not significantly alter the Ras/Raf/MAPK pathway compared with the effect of sorafenib alone.

Conclusion: Sorafenib/BEZ235 combination has potent anti-HCC cell activity. This anti-tumor activity is most likely multi-factorial, mainly involving PI3K down-regulation and Akt, mTOR and S6K dephosphorylation. Combined inhibition of PI3K/Akt/mTOR and Ras/Raf/MAPK pathways enhances sorafenib inhibition of HCC. The results of these in vitro studies suggest that trials of combined sorafenib and BEZ235 in the treatment of HCC should be considered.