Z Gastroenterol 2018; 56(01): E2-E89
DOI: 10.1055/s-0037-1612825
Poster Visit Session IV Tumors, Liver Surgery and Transplantation – Saturday, January 27, 2018, 8:30am – 9:15am, Foyer area West Wing
Georg Thieme Verlag KG Stuttgart · New York

The pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice

Authors

  • K Evert

    1   University of Regensburg, Institute of Pathology, Regensburg

  • S Zhang

    2   University of California, Department of Bioengineering and Therapeutic Sciences and Liver Center, San Francisco
    3   Second Military Medical University, Department of Pathology, Shanghai

  • B Fan

    2   University of California, Department of Bioengineering and Therapeutic Sciences and Liver Center, San Francisco

  • L Che

    2   University of California, Department of Bioengineering and Therapeutic Sciences and Liver Center, San Francisco

  • M Pilo

    4   University of Greifswald, Institute of Pathology, Greifswald

  • A Cigliano

    4   University of Greifswald, Institute of Pathology, Greifswald

  • S Ribback

    4   University of Greifswald, Institute of Pathology, Greifswald

  • F Dombrowski

    4   University of Greifswald, Institute of Pathology, Greifswald

  • X Chen

    2   University of California, Department of Bioengineering and Therapeutic Sciences and Liver Center, San Francisco

  • M Evert

    1   University of Regensburg, Institute of Pathology, Regensburg

  • D Calvisi

    4   University of Greifswald, Institute of Pathology, Greifswald
Further Information

Publication History

Publication Date:
03 January 2018 (online)

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Question:

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive tumor without effective treatment options. MLN0128, a second-generation pan-mTOR inhibitor, has shown efficacy in the treatment of multiple experimental cancer types.

Methods:

In the present study, we evaluated the therapeutic potential of MLN0128 and compared it with gemcitabine/oxaliplatin (the standard therapeutic option for this tumor entity) in a novel ICC mouse model ad hoc generated. Specifically, we established a novel ICC model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A) in the mouse liver.

Results:

We found that co-expression of myr-AKT and YapS127A promoted rapid 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, MLN0128 administration in the early stage of AKT/YapS127A carcinogenesis resulted in disease stabilization. Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling in vivo, inducing strong ICC cell apoptosis and only marginally affecting proliferation. Equivalent results were obtained when MLN0128 was administered to a collection of human ICC cell lines.

Conclusions:

In conclusion, this study strongly suggests that second-generation mTOR inhibitors may be beneficial for the treatment of ICC, especially in the subset of tumors exhibiting activated AKT/mTOR cascade.