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Pan-mTOR inhibitor MLN0128 is effective against intrahepatic cholangiocarcinoma in mice
Shanshan Zhang1, Xinhua Song2, Dan Cao3
1Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
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.
Insights
A novel mouse model for intrahepatic cholangiocarcinoma (ICC) was developed. The mTOR inhibitor MLN0128 demonstrated anti-neoplastic potential, showing promise against ICC, particularly in tumors with an activated AKT/mTOR pathway.
Area of Science:
- Oncology
- Molecular Biology
- Preclinical Cancer Research
Background:
- Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with limited therapeutic options.
- The pan-mTOR inhibitor MLN0128 has shown efficacy across various tumor types.
- There is a need for novel treatment strategies for ICC, especially for chemo-resistant cases.
Purpose of the Study:
- To evaluate the therapeutic potential of MLN0128 compared to gemcitabine/oxaliplatin in a novel ICC mouse model.
- To investigate the role of mTORC1 and mTORC2 in ICC development driven by AKT and Yap.
- To assess the efficacy of MLN0128 in both early and late stages of ICC progression.
Main Methods:
- Development of a novel ICC mouse model using hydrodynamic transfection of AKT and Yap protooncogenes (AKT/YapS127A).
- In vivo administration of MLN0128 and gemcitabine/oxaliplatin in tumor-bearing mice.
- In vitro studies using human ICC cell lines and molecular analyses including immunohistochemistry and immunoblotting.
Main Results:
- The AKT/YapS127A mouse model successfully recapitulated ICC development, requiring both mTORC1 and mTORC2.
- Gemcitabine/oxaliplatin showed limited efficacy in late-stage ICC.
- MLN0128 induced partial tumor regression in late-stage ICC and disease stabilization in early-stage disease, primarily by promoting apoptosis via AKT/mTOR signaling inhibition.
Conclusions:
- mTOR kinase inhibitors like MLN0128 may offer a beneficial treatment strategy for ICC.
- MLN0128 shows potential efficacy even in tumors resistant to standard chemotherapy (gemcitabine/oxaliplatin).
- The activated AKT/mTOR cascade is a potential predictive biomarker for response to MLN0128 in ICC.
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