| Autor: |
Kurma K; Institute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, France., Zeybek Kuyucu A; Institute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, France., Roth GS; Institute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, France.; Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, 38700 Grenoble, France., Sturm N; Pathology and Cytology Department, CHU Grenoble Alpes, 38700 Grenoble, France.; T-RAIG, TIMC, University Grenoble-Alpes/CNRS UMR5525, 38700 La Tronche, France., Mercey-Ressejac M; Institute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, France.; Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, 38700 Grenoble, France., Abbadessa G; ArQule Inc., Burlington, MA 01803, USA., Yu Y; ArQule Inc., Burlington, MA 01803, USA., Lerat H; Unité Mixte de Service hTAG, Grenoble Alpes University, Inserm US046, CNRS UAR2019, 38700 La Tronche, France., Marche PN; Institute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, France., Decaens T; Institute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, France.; Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, 38700 Grenoble, France., Macek Jilkova Z; Institute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, France.; Hepato-Gastroenterology and Digestive Oncology Department, CHU Grenoble Alpes, 38700 Grenoble, France. |
| Abstrakt: |
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. |
