SYNERGISTIC ANTI-TUMOR EFFECT OF SORAFENIB IN COMBINATION WITH AKT INHIBITORS IN HEPATOCELLULAR CARCINOMA

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Abstract

Background

Sorafenib is currently the only approved agent for hepatocellular carcinoma (HCC). However, its clinical efficacy in HCC is limited. Previous studies indicate that compensatory activation of AKT may contribute to the resistance to sorafenib. We hypothesized that combination of sorafenib and AKT inhibitors could enhance the antitumor effect of sorafenib in HCC.

Methods

We analyzed the cellular and molecular effects of sorafenib in combination with inhibitors of AKT in human HCC cell lines, and evaluated their combinational effects against HCC in vitro and in vivo.

Results

HCC cells, including Huh7, Hep3B, and SKhep1 cells, expressed high levels of p-AKT in a prompt and sustained manner upon treated with sorafenib. Down-regulation of AKT by siRNA or inhibition of phospho-AKT by AKT inhibitors (MK-2206 or perifosine) enhanced the anti-proliferative effect of sorafenib in cultured HCC cells. The combination indexes of sorafenib and AKT inhibitors were <1 in multiple HCC cells, indicating a synergistic antitumor effect for the combination. Combination of sorafenib and AKT inhibitors induced more significant apoptosis in HCC cells, as quantified by flow cytometry and cleavage of PARP, than either single agent. In the subcutaneous xenograft model of Huh7 cells, the combination of sorafenib and MK-2206 resulted in a better effect in delaying the growth of HCC xenografts.

Conclusions

Inhibition of AKT by AKT inhibitors improved the antitumor effect of sorafenib against HCC in vitro and in vivo. Combination of AKT inhibitors and sorafenib warrants further consideration for clinical development in HCC. (The study was supported by NSC97-2628-B-002-004-MY3 and NSC100-2325-B-002-043-.)

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