Efficacy of AKT inhibitor ARQ 092 compared with sorafenib in a cirrhotic rat model with hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related mortality worldwide. AKT pathway has been found activated in 50% of HCC cases, making it promising target. Therefore we assess efficacy of the allosteric AKT inhibitor ARQ 092 compared to untreated control and to standard treatment, Sorafenib, in vitro and in vivo. <p>ARQ 092 blocked phosphorylation of AKT in vitro and strongly inhibited cell growth with significantly higher potency than Sorafenib. Similarly, apoptosis and cell migration were strongly reduced by ARQ 092 in vitro. To mimic human advanced HCC, we used diethylnitrosamine-induced cirrhotic rat model with fully developed HCC. MRI analyses showed that ARQ 092 significantly reduced overall tumor size. Furthermore, number of tumors was decreased by ARQ 092, which was associated with increased apoptosis and decreased proliferation. Tumor contrast enhancement was significantly decreased in the ARQ 092 group. Moreover, on tumor tissue sections, we observed a vascular normalization nd a significant decrease in fibrosis in surrounding liver of animals treated with ARQ 092. Finally, pAKT/AKT levels in ARQ 092 treated tumors were reduced, followed by down regulation of actors of AKT downstream signaling pathway: pmTOR, pPRAS40, pPLC1 and pS6K1.</p> <p>In conclusion, we demonstrated that ARQ 092 blocks AKT phosphorylation in vitro and in vivo. In HCC-rat model, ARQ 092 was well tolerated, showed anti-fibrotic effect and had stronger antitumor effect than Sorafenib. Our results confirm the importance of targeting AKT in HCC.

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