Copyright: Macek Jilkova et al. This is an open-access article distributed under the terms of the Creative Commons AttributionLicense 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACTThe prognosis of patients with advanced hepatocellular carcinoma (HCC) is very poor. The AKT pathway is activated in almost half of HCC cases and in addition, long term exposure to conventional drug treatment of HCC, sorafenib, often results in overactivation of AKT, leading to HCC resistance. Therefore, it is important to assess the safety and the efficacy of selective allosteric AKT inhibitor ARQ 092 (Miransertib) in combination with sorafenib.Here, we demonstrated in vitro that the combination of ARQ 092 with sorafenib synergistically suppressed proliferation, promoted apoptosis, and reduced migration. To test the effect of the combination in vivo, rats with diethylnitrosamine-induced cirrhosis and fully developed HCC were randomized and treated with vehicle, sorafenib, ARQ 092 or the combination of ARQ 092 with sorafenib; (n=7/group) for 6 weeks. Tumor progression, size of tumors and the mean tumor number were significantly reduced by the combination treatment compared to the control or single treatments. This effect was associated with a significant increase in apoptotic response and reduction in proliferation and angiogenesis. Sirius red staining showed a decrease in liver fibrosis. Moreover, treatments improved immune response in blood and in tumor microenvironment.Thus, the combination of ARQ 092 with sorafenib potentiates inhibition of tumor progression and gives the possibility of therapeutic improvement for patients with advanced HCC.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer in adults and has one of the highest mortality rates of solid cancers. Ninety percent of HCCs are associated with liver fibrosis or cirrhosis developed from chronic liver injuries. The immune system of the liver contributes to the severity of the necrotic-inflammatory tissue damage, the establishment of fibrosis and cirrhosis, and the disease progression towards HCC. Immunotherapies have emerged as an exciting strategy for HCC treatment, but their effect is limited, and an extensive translation research is urgently needed to enhance anti-tumor efficacy and clinical success. Establishing HCC animal models that are analogous to human disease settings, i.e., mimicking the tumor microenvironment of HCC, is extremely challenging. Hence, this review discusses different animal models of HCC by summarizing their advantages and their limits with a specific focus on the role of the immune system and tumor microenvironment.