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Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer histotype, characterized by high biological aggressiveness and scarce treatment options. Recently, we have established a clinically relevant murine HCC model by co-expressing activated forms of v-akt murine thymoma vi...

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Autores principales: Liu, Xianqiong, Hu, Junjie, Song, Xinhua, Utpatel, Kirsten, Zhang, Yi, Wang, Pan, Lu, Xinjun, Zhang, Jie, Xu, Meng, Su, Tao, Che, Li, Wang, Jingxiao, Evert, Matthias, Calvisi, Diego F., Chen, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679026/
https://www.ncbi.nlm.nih.gov/pubmed/31277283
http://dx.doi.org/10.3390/cancers11070930
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author Liu, Xianqiong
Hu, Junjie
Song, Xinhua
Utpatel, Kirsten
Zhang, Yi
Wang, Pan
Lu, Xinjun
Zhang, Jie
Xu, Meng
Su, Tao
Che, Li
Wang, Jingxiao
Evert, Matthias
Calvisi, Diego F.
Chen, Xin
author_facet Liu, Xianqiong
Hu, Junjie
Song, Xinhua
Utpatel, Kirsten
Zhang, Yi
Wang, Pan
Lu, Xinjun
Zhang, Jie
Xu, Meng
Su, Tao
Che, Li
Wang, Jingxiao
Evert, Matthias
Calvisi, Diego F.
Chen, Xin
author_sort Liu, Xianqiong
collection PubMed
description Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer histotype, characterized by high biological aggressiveness and scarce treatment options. Recently, we have established a clinically relevant murine HCC model by co-expressing activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and oncogene c-mesenchymal-epithelial transition (c-Met) proto-oncogenes in the mouse liver via hydrodynamic tail vein injection (AKT/c-MET mice). Tumor cells from these mice demonstrated high activity of the AKT/ mammalian target of rapamycin (mTOR) and Ras/ Mitogen-activated protein kinase (MAPK) signaling cascades, two pathways frequently co-induced in human HCC. Methods: Here, we investigated the therapeutic efficacy of sorafenib, regorafenib, the MEK inhibitor PD901 as well as the pan-mTOR inhibitor MLN0128 in the AKT/c-Met preclinical HCC model. Results: In these mice, neither sorafenib nor regorafenib demonstrated any efficacy. In contrast, administration of PD901 inhibited cell cycle progression of HCC cells in vitro. Combined PD901 and MLN0128 administration resulted in a pronounced growth constraint of HCC cell lines. In vivo, treatment with PD901 or MLN0128 alone moderately slowed HCC growth in AKT/c-MET mice. Importantly, the simultaneous administration of the two drugs led to a stable disease with limited tumor progression in mice. Mechanistically, combined mitogen-activated extracellular signal-regulated kinase (MEK) and mTOR inhibition resulted in a stronger cell cycle inhibition and growth arrest both in vitro and in vivo. Conclusions: Our study indicates that combination of MEK and mTOR inhibitors might represent an effective therapeutic approach against human HCC.
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spelling pubmed-66790262019-08-19 Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma Liu, Xianqiong Hu, Junjie Song, Xinhua Utpatel, Kirsten Zhang, Yi Wang, Pan Lu, Xinjun Zhang, Jie Xu, Meng Su, Tao Che, Li Wang, Jingxiao Evert, Matthias Calvisi, Diego F. Chen, Xin Cancers (Basel) Article Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer histotype, characterized by high biological aggressiveness and scarce treatment options. Recently, we have established a clinically relevant murine HCC model by co-expressing activated forms of v-akt murine thymoma viral oncogene homolog (AKT) and oncogene c-mesenchymal-epithelial transition (c-Met) proto-oncogenes in the mouse liver via hydrodynamic tail vein injection (AKT/c-MET mice). Tumor cells from these mice demonstrated high activity of the AKT/ mammalian target of rapamycin (mTOR) and Ras/ Mitogen-activated protein kinase (MAPK) signaling cascades, two pathways frequently co-induced in human HCC. Methods: Here, we investigated the therapeutic efficacy of sorafenib, regorafenib, the MEK inhibitor PD901 as well as the pan-mTOR inhibitor MLN0128 in the AKT/c-Met preclinical HCC model. Results: In these mice, neither sorafenib nor regorafenib demonstrated any efficacy. In contrast, administration of PD901 inhibited cell cycle progression of HCC cells in vitro. Combined PD901 and MLN0128 administration resulted in a pronounced growth constraint of HCC cell lines. In vivo, treatment with PD901 or MLN0128 alone moderately slowed HCC growth in AKT/c-MET mice. Importantly, the simultaneous administration of the two drugs led to a stable disease with limited tumor progression in mice. Mechanistically, combined mitogen-activated extracellular signal-regulated kinase (MEK) and mTOR inhibition resulted in a stronger cell cycle inhibition and growth arrest both in vitro and in vivo. Conclusions: Our study indicates that combination of MEK and mTOR inhibitors might represent an effective therapeutic approach against human HCC. MDPI 2019-07-03 /pmc/articles/PMC6679026/ /pubmed/31277283 http://dx.doi.org/10.3390/cancers11070930 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Xianqiong
Hu, Junjie
Song, Xinhua
Utpatel, Kirsten
Zhang, Yi
Wang, Pan
Lu, Xinjun
Zhang, Jie
Xu, Meng
Su, Tao
Che, Li
Wang, Jingxiao
Evert, Matthias
Calvisi, Diego F.
Chen, Xin
Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma
title Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma
title_full Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma
title_fullStr Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma
title_full_unstemmed Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma
title_short Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma
title_sort combined treatment with mek and mtor inhibitors is effective in in vitro and in vivo models of hepatocellular carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679026/
https://www.ncbi.nlm.nih.gov/pubmed/31277283
http://dx.doi.org/10.3390/cancers11070930
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