Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting...

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Autophagy is vital for cellular homeostasis and a target for cancer therapy.
• Mechanistic target of rapamycin (mTOR) regulates autophagy and is a key therapeutic target.
• Hyperactivating autophagy can induce cancer cell death.

Purpose of the Study:

• To identify potential mTOR complex 1 (mTORC1) inhibitors using structure-based virtual screening.
• To evaluate lomitapide's efficacy in inducing autophagy-dependent cancer cell death.
• To assess lomitapide's synergistic effects with immune checkpoint inhibitors in preclinical cancer models.

Main Methods:

• Structure-based virtual screening to identify mTORC1 inhibitors.
• In vitro assays to confirm direct mTORC1 inhibition by lomitapide.
• In vitro and in vivo experiments using cancer cell lines, organoids, and tumor xenografts.
• Preclinical syngeneic tumor models to evaluate combination therapy with immune checkpoint blocking antibodies.

Main Results:

• Lomitapide was identified as a potential mTORC1 inhibitor.
• Lomitapide directly inhibits mTORC1, decreasing mTOR signaling and inducing autophagy-dependent cancer cell death.
• Lomitapide suppressed cancer cell growth, viability, and tumor xenografts, with elevated autophagy.
• Combination therapy with lomitapide and immune checkpoint blockers synergistically inhibited tumor growth in preclinical models.

Conclusions:

• Lomitapide directly inhibits mTORC1 and induces autophagy-dependent cancer cell death.
• Lomitapide demonstrates potential as a repurposed therapeutic agent for cancer treatment.
• Lomitapide enhances anti-tumor immunity, complementing immune checkpoint blockade therapies.