Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma
AbstractBackground: 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
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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.
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 DF, Chen X. Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma. Cancers. 2019; 11(7):930.Chicago/Turabian Style
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. 2019. "Combined Treatment with MEK and mTOR Inhibitors is Effective in In Vitro and In Vivo Models of Hepatocellular Carcinoma." Cancers 11, no. 7: 930.
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