Zhang, Shanshan and Song, Xinhua and Cao, Dan and Xu, Zhong and Fan, Biao and Che, Li and Hu, Junjie and Chen, Bin and Dong, Mingjie and Pilo, Maria G. and Cigliano, Antonio and Evert, Katja and Ribback, Silvia and Dombrowski, Frank and Pascale, Rosa M. and Cossu, Antonio and Vidili, Gianpaolo and Porcu, Alberto and Simile, Maria M. and Pes, Giovanni M. and Giannelli, Gianluigi and Gordan, John and Wei, Lixin and Evert, Matthias and Cong, Wenming and Calvisi, Diego F. and Chen, Xin (2017) Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice. JOURNAL OF HEPATOLOGY, 67 (6). pp. 1194-1203. ISSN 0168-8278, 1600-0641
Full text not available from this repository. (Request a copy)Abstract
Background & Aims: Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. We evaluated the therapeutic potential of MLN0128 vs. gemcitabine/oxaliplatin in a novel ICC mouse model. Methods: We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis. Gemcitabine/oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor-bearing mice to study their anti-tumor efficacy in vivo. Multiple human ICC cell lines were used for in vitro experiments. Hematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied for the characterization and mechanistic study. Results: Co-expression of myr-AKT and YapS127A promoted ICC development in mice. Both mTORC1 and mTORC2 complexes were required for AKT/YapS127A ICC development. Gemcitabine/oxaliplatin had limited efficacy in treating late stage AKT/YapS127A ICC. In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A cholangiocarcinogenesis. Furthermore, when MLN0128 was administered in the early stage of AKT/YapS127A carcinogenesis, it led to disease stabilization. Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling both in vivo and in vitro, inducing strong ICC cell apoptosis and only marginally affecting proliferation. Conclusions: This study suggests that mTOR kinase inhibitors may be beneficial for the treatment of ICC, even in tumors that are resistant to standard of care chemotherapeutics, such as gemcitabine/oxaliplatin-based regimens, especially in the subset of tumors exhibiting activated AKT/mTOR cascade. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ANTITUMOR-ACTIVITY; KINASE INHIBITOR; CANCER; AKT; PATHWAY; THERAPY; MODELS; HEPATOCARCINOGENESIS; COACTIVATION; GENERATION; Intrahepatic cholangiocarcinoma; Dual mTOR inhibitor; Targeted therapy; Gemcitabine; Translational medicine; Mouse model; MLN0128 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:19 |
| Last Modified: | 18 Feb 2019 12:36 |
| URI: | https://pred.uni-regensburg.de/id/eprint/1802 |
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