Targeted therapy for mTORC1-driven tumours through HDAC inhibition by exploiting innate vulnerability of mTORC1...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Mechanistic target of rapamycin complex 1 (mTORC1) signaling is crucial in cancer development and progression.
• Current mTORC1 inhibitor therapies show limited clinical efficacy for many cancers.

Purpose of the Study:

• To evaluate histone deacetylase (HDAC) inhibitors as anti-tumor agents for mTORC1-driven cancers.
• To investigate the therapeutic potential of HDAC inhibitors in a novel mouse model of lymphangiosarcoma.

Main Methods:

• Development of a Tsc1-deficient endothelial cell mouse model exhibiting hyperactive mTORC1.
• Assessment of various HDAC inhibitors (class I, IIa, IIb, pan) on tumor cell viability in vitro and in vivo.
• Analysis of cell death mechanisms, including autophagy, apoptosis, reactive oxygen species, and endoplasmic reticulum stress.

Main Results:

• HDAC inhibitors, particularly class I inhibitors, induced significant tumor cell death, contrasting with the cytostatic effects of mTORC1 inhibitors.
• HDAC inhibitor-induced cell death was dependent on elevated autophagy and not caspase-dependent apoptosis.
• SAHA treatment led to increased reactive oxygen species and endoplasmic reticulum stress, contributing to autophagic cell death in an mTORC1-dependent manner.

Conclusions:

• HDAC inhibitors represent a promising alternative therapeutic strategy for mTORC1-driven cancers.
• The findings suggest a novel mechanism of tumor suppression involving autophagy and stress pathways, independent of direct mTORC1 inhibition.