Background Identifying therapeutic approaches to treat cancer is laborious, expensive, and often inefficient. Drug repurposing or repositioning in oncology refers to the application of drugs, which are already approved for other medical applications, in treating cancer.1 Moreover, in order to enhance therapeutic benefits, repurposed drugs are often combined with frequent administrations of low-dose chemotherapy/immunotherapy. Recent advancements in artificial intelligence (AI) technology have led to the development of in silico drug discovery approaches. Therefore, therapeutic discovery through a drug repurposing strategy aided by these technological advancements can potentially accelerate studies into clinical trials more rapidly compared to that using newly developed drugs.
Methods In this study, we employed an AI driven structure-based model (ERSTE-Explorer) to identify an mTOR inhibitor candidate. Using in vitro biochemical and cellular experiments as well as transcriptome sequencing analyses, we identified lomitapide, an inhibitor of hepatic microsomal triglyceride transfer protein (MTTP) approved for the homozygous familial hypercholesterolemia (HoFH) is an mTOR inhibitor.2 To validate anticancer effect of lomitapide in vivo, we used tumor xenograft model and patient-derived colorectal cancer organoids for clinical relavance. Furthermore, potential synergistic effects were confirmed by combining of lomitapide and immune checkpoint blocking antibodies to inhibit tumor growth in murine MC38 or B16-F10 preclinical syngeneic tumor models.3
Results 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.4, 5Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor (figure 1). Our results showed that lomitapide directly inhibits mTORC1 in vitro (figure 1) and induces autophagy-dependent cancer cell death by decreasing mTOR signaling (figure 2), thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) (figure 3) and tumor xenografts (figure 4). Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids (figure 5). Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC38 or B16-F10 preclinical syngeneic tumor models (figure 6).
Conclusions Our results elucidate the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights that the U.S. FDA-approved drug, lomitapide, can be potentially repurposed for the treatment of cancer.
Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Disco. 2019;18:41–58.
Vuorio A, Tikkanen MJ, Kovanen PT. Inhibition of hepatic microsomal triglyceride transfer protein – a novel therapeutic option for treatment of homozygous familial hypercholesterolemia. Vasc Health Risk Manag. 2014;10:263–70.
Li H, Li X, Liu S, Guo L, Zhang B, Zhang J, et al. Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell-intrinsic PD-1. Hepatology. 2017;66:1920–33.
Lamb CA, Yoshimori T, Tooze SA. The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol. 2013;14:759–74.
Amaravadi R, Kimmelman AC, White E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016;30:1913–30.
Ethics Approval All mice were housed in a pathogen-free animal facility at KAIST Laboratory Animal Resource Center. The animals were maintained in a temperature/humidity-controlled room on a 12 h light/12 h dark cycle and fed a standard chow diet. All experiments involving animals were conducted according to the ethical policies and procedures approved by the Committee for Animal Care at KAIST.
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