Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model

• Published in: International journal of molecular sciences Vol. 23; no. 24; p. 16206
• Main Authors: Kurma, Keerthi, Zeybek Kuyucu, Ayca, Roth, Gaël S, Sturm, Nathalie, Mercey-Ressejac, Marion, Abbadessa, Giovanni, Yu, Yi, Lerat, Herve, Marche, Patrice N, Decaens, Thomas, Macek Jilkova, Zuzana
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19.12.2022; MDPI
• Subjects: AKT pathway; AKT protein; Allosteric properties; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer; Carcinoma, Hepatocellular - metabolism; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation; Cirrhosis; DEN-induced cirrhotic rat model of HCC; Diethylnitrosamine; Fibrosis; HCC; Hepatitis; Hepatocellular carcinoma; Human health and pathology; Hépatology and Gastroenterology; Kinases; Life Sciences; Liver; Liver cancer; Liver cirrhosis; Liver Cirrhosis - drug therapy; Liver diseases; Liver Neoplasms - metabolism; Medical prognosis; Model testing; Mutation; Niacinamide - pharmacology; Niacinamide - therapeutic use; Pharmaceutical sciences; Pharmacology; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Proto-Oncogene Proteins c-akt - metabolism; Rats; Sorafenib - pharmacology; Sorafenib - therapeutic use; Targeted cancer therapy; Tumors; Tyrosine; vevorisertib; HCC; DEN-induced cirrhotic rat model of HCC; fibrosis; liver; vevorisertib; AKT pathway
• DOI: 10.3390/ijms232416206
• ISSN: 1422-0067; 1661-6596

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The AKT pathway is often activated in HCC cases, and a longer exposure to tyrosine kinase inhibitors such as sorafenib may lead to over-activation of the AKT pathway, leading to HCC resistance. Here, we studied the efficacy of a new generation of allosteric AKT inhibitor, vevorisertib, alone or in combination with sorafenib. To identify specific adverse effects related to the background of cirrhosis, we used a diethylnitrosamine (DEN)-induced cirrhotic rat model. Vevorisertib was tested in vitro on Hep3B, HepG2, HuH7 and PLC/PRF cell lines. Rats were treated weekly with intra-peritoneal injections of DEN for 14 weeks to obtain cirrhosis with fully developed HCC. After that, rats were randomized into four groups (n = 7/group): control, sorafenib, vevorisertib and the combination of vevorisertib + sorafenib, and treated for 6 weeks. Tumor progression was followed by MRI. We demonstrated that the vevorisertib is a highly potent treatment, blocking the phosphorylation of AKT. The tumor progression in the rat liver was significantly reduced by treatment with vevorisertib + sorafenib (49.4%) compared to the control group (158.8%, p < 0.0001). Tumor size, tumor number and tumor cell proliferation were significantly reduced in both the vevorisertib group and vevorisertib + sorafenib groups compared to the control group. Sirius red staining showed an improvement in liver fibrosis by vevorisertib and the combination treatment. Moreover, vevorisertib + sorafenib treatment was associated with a normalization in the liver vasculature. Altogether, vevorisertib as a single agent and its combination with sorafenib exerted a strong suppression of tumor progression and improved liver fibrosis. Thus, results provide a rationale for testing vevorisertib in clinical settings and confirm the importance of targeting AKT in HCC.