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

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. 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.

• Authors: Shanshan Zhang, Xinhua Song, Dan Cao, Zhong Xu, Biao Fan, Li Che, Junjie Hu, Bin Chen, Mingjie Dong, Maria G Pilo, Antonio Cigliano, Katja Evert, Silvia Ribback, Frank Dombrowski, Rosa M Pascale, Antonio Cossu, Gianpaolo Vidili, Alberto Porcu, Maria M Simile, Giovanni M Pes, Gianluigi Giannelli, John Gordan, Lixin Wei, Matthias Evert, Wenming Cong, Diego F Calvisi, Xin Chen
• Journal: Journal of hepatology (J Hepatol) Vol. 67 Issue 6 Pg. 1194-1203 (12 2017) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 28733220 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Antineoplastic Agents
• Cell Cycle Proteins
• Phosphoproteins
• Protein Kinase Inhibitors
• YAP-Signaling Proteins
• Yap1 protein, mouse
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Animals
• Antineoplastic Agents (therapeutic use)
• Bile Duct Neoplasms (drug therapy, etiology, pathology)
• Cell Cycle Proteins
• Cholangiocarcinoma (drug therapy, etiology, pathology)
• Female
• Humans
• Mechanistic Target of Rapamycin Complex 1 (physiology)
• Mechanistic Target of Rapamycin Complex 2 (physiology)
• Mice
• Phosphoproteins (genetics)
• Protein Kinase Inhibitors (therapeutic use)
• Proto-Oncogene Proteins c-akt (genetics)
• Signal Transduction (physiology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, physiology)
• YAP-Signaling Proteins