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DOI: 10.1055/s-0037-1612825
The pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice
Publication History
Publication Date:
03 January 2018 (online)
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.