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

1
Pharmacy Faculty, Hubei University of Chinese Medicine Wuhan, Wuhan 430065, China
2
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA 94143, USA
3
Institute of Pathology, University of Regensburg, Regensburg 93053, Germany
4
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
5
Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
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Department of Hepatic Surgery, the First Aliated Hospital, Sun Yat-sen University, No. 58 Zhongshan 2nd Road, Guangzhou 510080, China
7
Department of Thoracic Oncology II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
8
Department of General Surgery, the Second Hospital of Xi’an Jiaotong University, Xi’an Jiaotong University, Xi’an 710061, China
*
Authors to whom correspondence should be addressed.
Xianqiong Liu and Junjie Hu contributed equally to this work.
Cancers 2019, 11(7), 930; https://doi.org/10.3390/cancers11070930
Received: 28 January 2019 / Revised: 25 June 2019 / Accepted: 27 June 2019 / Published: 3 July 2019
(This article belongs to the Special Issue Models of Experimental Liver Cancer)
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PDF [6965 KB, uploaded 3 July 2019]
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Abstract

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. View Full-Text
Keywords: hepatocellular carcinoma; MEK inhibitor; pan-mTOR inhibitor; PD901; MLN0128; cell proliferation; apoptosis hepatocellular carcinoma; MEK inhibitor; pan-mTOR inhibitor; PD901; MLN0128; cell proliferation; apoptosis
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Liu, X.; Hu, J.; Song, X.; Utpatel, K.; Zhang, Y.; Wang, P.; Lu, X.; Zhang, J.; Xu, M.; Su, T.; Che, L.; Wang, J.; Evert, M.; Calvisi, D.F.; Chen, X. Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma. Cancers 2019, 11, 930.

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