1. Targeted therapy for mTORC1-driven tumours through HDAC inhibition by exploiting innate vulnerability of mTORC1 hyper-activation
- Author
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Michael Haas, Syn Kok Yeo, Shaogang Sun, Chenran Wang, Jun-Lin Guan, and Fuchun Yang
- Subjects
Cancer Research ,Programmed cell death ,medicine.medical_treatment ,Antineoplastic Agents ,Apoptosis ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,Article ,Targeted therapy ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Targeted therapies ,In vivo ,medicine ,Autophagy ,Animals ,Molecular Targeted Therapy ,030304 developmental biology ,Cell Proliferation ,0303 health sciences ,Chemistry ,Endoplasmic reticulum ,Lymphangiosarcoma ,Neoplasms, Experimental ,In vitro ,Histone Deacetylase Inhibitors ,Disease Models, Animal ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Histone deacetylase ,biological phenomena, cell phenomena, and immunity - Abstract
Backgound The mechanistic target of rapamycin complex 1 (mTORC1) is important in the development and progression of many cancers. Targeted cancer therapy using mTORC1 inhibitors is used for treatment of cancers; however, their clinical efficacies are still limited. Methods We recently created a new mouse model for human lymphangiosarcoma by deleting Tsc1 in endothelial cells and consequent hyper-activation of mTORC1. Using Tsc1iΔEC tumour cells from this mouse model, we assessed the efficacies of histone deacetylase (HDAC) inhibitors as anti-tumour agents for mTORC1-driven tumours. Results Unlike the cytostatic effect of mTORC1 inhibitors, HDAC inhibitors induced Tsc1iΔEC tumour cell death in vitro and their growth in vivo. Analysis of several HDAC inhibitors suggested stronger anti-tumour activity of class I HDAC inhibitor than class IIa or class IIb inhibitors, but these or pan HDAC inhibitor SAHA did not affect mTORC1 activation in these cells. Moreover, HDAC inhibitor-induced cell death required elevated autophagy, but was not affected by disrupting caspase-dependent apoptosis pathways. We also observed increased reactive oxygen species and endoplasmic reticulum stress in SAHA-treated tumour cells, suggesting their contribution to autophagic cell death, which were dependent on mTORC1 hyper-activation. Conclusion These studies suggest a potential new treatment strategy for mTORC1-driven cancers like lymphangiosarcoma through an alternative mechanism.
- Published
- 2019