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Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice.

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机构： [1]Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China [2]Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China [3]Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China [4]Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China [5]Department of Gastroenterology, Guizhou Provincial People’s Hospital, Guizhou, China [6]Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China [7]Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA [8]School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China [9]Department of Pediatrics and Institute for Computational Health Sciences, University of California, San Francisco, CA, USA [10]Department of Gastroenterology, 307 Hospital of PLA, Beijing, China [11]Institute of Pathology, University of Greifswald, Greifswald, Germany [12]Institute of Pathology, University of Regensburg, Regensburg, Germany [13]Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy [14]Unit of Pathology, Azienda Ospedaliero Universitaria Sassari, Sassari, Italy [15]National Institute of Gastroenterology ‘‘S. de Bellis”, Research Hospital, Castellana Grotte, Italy [16]Department of Medicine, University of California, San Francisco, CA, USA

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关键词： Intrahepatic cholangiocarcinoma Dual mTOR inhibitor Targeted therapy Gemcitabine Translational medicine Mouse model MLN0128

摘要：

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. 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. 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. 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. Lay summary: We established a novel mouse model of intrahepatic cholangiocarcinoma (ICC). Using this new preclinical model, we evaluated the therapeutic potential of mTOR inhibitor MLN0128 vs. gemcitabine/oxaliplatin (the standard chemotherapy for ICC treatment). Our study shows the anti-neoplastic potential of MLN0128, suggesting that it may be superior to gemcitabine/oxaliplatin-based chemotherapy for the treatment of ICC, especially in the tumors exhibiting activated AKT/mTOR cascade. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

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出版当年[2017]版：

大类 | 1 区

医学

小类 | 1 区胃肠肝病学

最新[2023]版：

大类 | 1 区

医学

小类 | 1 区胃肠肝病学

第一作者：

第一作者机构： [1]Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China [2]Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China [7]Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA

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通讯作者：

通讯机构： [1]Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China [7]Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA [8]School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, China [11]Institute of Pathology, University of Greifswald, Greifswald, Germany [*1]Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China. [*2]Institut für Pathologie, Universit?tsmedizin Greifswald, Friedrich-Loeffler-Strasse 23e, 17489 Greifswald, Germany. [*3]UCSF, 513 Parnassus Avenue, San Francisco, CA 94143, USA.

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Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice.

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