Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model
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, w...
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| Format: | Article |
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/24/16206 |
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| author | Keerthi Kurma Ayca Zeybek Kuyucu Gaël S. Roth Nathalie Sturm Marion Mercey-Ressejac Giovanni Abbadessa Yi Yu Herve Lerat Patrice N. Marche Thomas Decaens Zuzana Macek Jilkova |
| author_facet | Keerthi Kurma Ayca Zeybek Kuyucu Gaël S. Roth Nathalie Sturm Marion Mercey-Ressejac Giovanni Abbadessa Yi Yu Herve Lerat Patrice N. Marche Thomas Decaens Zuzana Macek Jilkova |
| author_sort | Keerthi Kurma |
| collection | DOAJ |
| description | 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 (<i>n</i> = 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%, <i>p</i> < 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. |
| first_indexed | 2024-03-09T16:18:47Z |
| format | Article |
| id | doaj.art-64e2bed5795c4aeca0b01892157bc78e |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:18:47Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-64e2bed5795c4aeca0b01892157bc78e2023-11-24T15:34:49ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123241620610.3390/ijms232416206Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat ModelKeerthi Kurma0Ayca Zeybek Kuyucu1Gaël S. Roth2Nathalie Sturm3Marion Mercey-Ressejac4Giovanni Abbadessa5Yi Yu6Herve Lerat7Patrice N. Marche8Thomas Decaens9Zuzana Macek Jilkova10Institute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, FranceInstitute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, FranceInstitute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, FrancePathology and Cytology Department, CHU Grenoble Alpes, 38700 Grenoble, FranceInstitute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, FranceArQule Inc., Burlington, MA 01803, USAArQule Inc., Burlington, MA 01803, USAUnité Mixte de Service hTAG, Grenoble Alpes University, Inserm US046, CNRS UAR2019, 38700 La Tronche, FranceInstitute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, FranceInstitute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, FranceInstitute for Advanced Biosciences, University Grenoble Alpes, CNRS UMR5309, INSERM U1209, 38700 Grenoble, FranceHepatocellular 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 (<i>n</i> = 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%, <i>p</i> < 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.https://www.mdpi.com/1422-0067/23/24/16206HCCDEN-induced cirrhotic rat model of HCCliverfibrosisvevorisertibAKT pathway |
| spellingShingle | Keerthi Kurma Ayca Zeybek Kuyucu Gaël S. Roth Nathalie Sturm Marion Mercey-Ressejac Giovanni Abbadessa Yi Yu Herve Lerat Patrice N. Marche Thomas Decaens Zuzana Macek Jilkova Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model International Journal of Molecular Sciences HCC DEN-induced cirrhotic rat model of HCC liver fibrosis vevorisertib AKT pathway |
| title | Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model |
| title_full | Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model |
| title_fullStr | Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model |
| title_full_unstemmed | Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model |
| title_short | Effect of Novel AKT Inhibitor Vevorisertib as Single Agent and in Combination with Sorafenib on Hepatocellular Carcinoma in a Cirrhotic Rat Model |
| title_sort | effect of novel akt inhibitor vevorisertib as single agent and in combination with sorafenib on hepatocellular carcinoma in a cirrhotic rat model |
| topic | HCC DEN-induced cirrhotic rat model of HCC liver fibrosis vevorisertib AKT pathway |
| url | https://www.mdpi.com/1422-0067/23/24/16206 |
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