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

Abstract

Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC38 or B16-F10 preclinical syngeneic tumor models. These results elucidate the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.

Anti-Inflammatory Effects of Lipid-Lowering Drugs and Supplements—A Narrative Review

“…One case series of six HoFH patients on long-term lomitapide therapy showed carotid intima-media thickness stabilization or regression [ 168 ]. In addition, recent studies emphasize the potential anti-cancer effects of lomitapide [ 169 , 170 ].…”

The utility of 3D models to study cholesterol in cancer: Insights and future perspectives

“…Seeing that these peptides mimic the uptake process of LDL (LDLR-mediated endocytosis and transfer to the late endosomal/lysosomal compartment), this can be exploited to deliver anticancer molecules to lysosomes resulting in targeted drug delivery (114). In a different study, implicate the LDL-targeting drug lomitapide in facilitating hyperactivation of autophagy which suppresses tumor growth and increases cancer cell death in CRC organoids (115). This was attributed to direct inhibition of mammalian target of rapamycin (mTOR) kinase activity and consequent regulation of mTOR signaling.…”

“…In a different study, Lee et al. (2022) implicate the LDL-targeting drug lomitapide in facilitating hyperactivation of autophagy which suppresses tumor growth and increases cancer cell death in CRC organoids ( 115 ). This was attributed to direct inhibition of mammalian target of rapamycin (mTOR) kinase activity and consequent regulation of mTOR signaling.…”

“…This was attributed to direct inhibition of mammalian target of rapamycin (mTOR) kinase activity and consequent regulation of mTOR signaling. Interestingly lomitapide proved more effective than 5-fluorouracil in decreasing organoid viability hence potentiating the use of lomitapide as anticancer therapeutic in CRC ( 115 ).…”