Lipids include fats, waxes, sterols, and fat-soluble vitamins, among others. In recent years, there have been significant developments in our understanding of the role of lipids in carcinogenesis, the process by which normal cells transform into cancer cells1. Tumors occur when normal cells escape the processes that control their growth. Cancer cells have long been recognized to be characterized by elevated lipid synthesis, largely because dividing cells need lipids for their cell membranes, so it is logical to develop cancer therapies to target the rate-limiting steps of lipogenic reactions. There is an excellent review on how lipid metabolism is involved with cancer, with extensive background and informative illustrations2. Another review contains additional insights about the therapeutic promise and challenges of lipogenesis inhibitors3. This newsletter will focus on recent developments in lipogenic enzyme inhibitors for treating cancer.
Lipid metabolism in cancer cells.
Lipids are synthesized in adipocytes and hepatocytes. Some of them, like alpha-linolenic acid and linoleic acid, cannot be made de novo by mammals, and require dietary sources. Cancer cells tend to make their own lipids, which allows them to bypass some of the growth limitations that are imposed upon other cells. They do so with the assistance of elevated levels of rate-limiting lipogenic enzymes such as acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), ATP-citrate lyase (ACLY), and stearoyl CoA desaturase (SCD)4. Tumors use lipids in many ways beyond cell growth, including oncogenic signaling, highlighting the complexity of lipid metabolism in cancer. Tumor cells can increase de novo lipogenesis, fatty acid uptake, and fatty acid oxidation for energy production and lipid accumulation. Cancer alters lipid metabolism to modulate ferroptosis-mediated cell death, support metastasis, and interact with the tumor microenvironment2. Unfortunately, healthy tissues, particularly in the immune system, also need lipids, which limits the utility of metabolic inhibitors in general5.
Figure 1. Schematic showing fatty acid synthesis and key enzymes that may be potential drug targets.
Acetyl-CoA carboxylases (ACCs), present in two isoforms (ACC1, ACC2, also known as ACCα and ACCβ) are central enzymes in mammalian metabolism, mediating fatty acid synthesis, glycolysis, and other carbon conversions (Fig. 1). ACCs convert Acetyl-CoA into Malonyl-CoA6, and these enzymes are promising targets for cancer treatments. ACC levels are elevated in several cancer cells, and several small molecule inhibitors have reached various stages of clinical trials. ND-646 prevents the development of nonsmall cell lung cancer blocking both isoforms7,8. The liverspecific ND-654 was tested in mice, and found to decrease hepatocellular tumors11. When these inhibitors were tested along with standard-of-care chemotherapy, they inhibited tumor growth further than uncombined treatments8,9. Additional information on ACCs in disease regulation can be found in a recent review by Wang et al.10.
Fatty acid synthase
Fatty acid synthase (FAS) builds lipid carbon chains by adding consecutive acetyl groups, eventually resulting in palmitate (Fig. 1), and as such, this enzyme is another attractive target for inhibition to fight cancer. The upregulation of this enzyme has been associated with many types of cancers, and the FAS inhibitor Fasnall inhibits breast cancers in a mouse model, both alone and when combined with carboplatin11. However, Fasnall exemplifies the complexities involved with targeting a single metabolic pathway for cancer treatments. It seems to reduce half of in vitro breast cancer tumors, and increase the other half, leading to the recommendation that multiple metabolic pathways need to be targeted as a supplement to conventional treatment12. Omeprazole, a proton pump inhibitor available over the counter for heartburn control has been repurposed forcancer therapy, as it is a mild FAS inhibitor with few side effects. It is currently under a number of clinical trials for a variety of cancers2. Small interfering RNA (siRNA) are small pieces of RNA that can specifically inhibit protein production by binding to and inactivating specific mRNAs. One such siRNA targeting FASN translation has shown promising results in reducing tumors in a mouse model. A recent review covers targeting fatty acid metabolism for cancer cells under stress13.
ATP-citrate lyase (ACLY) converts citrate to acetyl-CoA and oxaloacetate (Fig. 1). This enzyme is highly expressed in a variety of cancers including lung14 and liver15, just as its inhibition suppresses them16. ACLY inhibitors in clinical and pre-clinical use as cancer treatments have been recently reviewed17. The ACLY inhibitor, BMS-303141, was successful in suppressing hepatocellular carcinoma (HCC)18. The small molecule ACLY inhibitor, ETC-1002 (bempedoic acid) has been thoroughly investigated in clinical trails for a wide variety of non-cancer diseases. ETC-1002 is modified in the liver, which is important for its activity9. Tissue specificity is a highly desirable property for cancer drugs. In combination with a fibroblast growth factor receptor1 (FGFR1) inhibitor PD173074, or with anti-programmed death-ligand 1 (PD-L1), ETC-1002 reduces hepatocellular carcinomas20. Gut-microbiome-derived acetyl-CoA may bypass ACLY inhibition, which is particularly important to recognize in treating liver cancers21. However, ETC-1002 can also activate AMPK, which slows lipogenesis through Acetyl-CoA carboxylase inhibition19. ETC-1002 warrants further study.
Palmitate is an abundant saturated fatty acid that can be desaturated by Stearoyl-CoA desaturase (SCD; Fig. 1) and generate palmitoleate22. The ratio of saturated and unsaturated fatty acid is delicately balanced in tumor cells, which can be killed by disrupting this balance23,24. Tumor growth can often outpace normal blood vessel formation, which requires tumors to develop a neovasculature for nutrients and oxygen. Depleted oxygen levels in cells can result in insufficient synthesis of unsaturated fatty acids which may lead to cell death25. New SCD inhibitors are being tested in pre-clinical cancer trials, with MF-438 and CAY 10566 can reduce ovarian cancer by altering the membrane phospholipid composition26. While A939572 decreases primary melanoma growth, it increased lung metastasis27, reminding us of how interconnected metabolic pathways can be.
Future perspectives – Lipid enzymes and metastasis
The process of metastasis is a complicated one, with few cells making it through the transition. Those that do are dependent on lipid metabolism, but the data regarding these lipid enzymes effect on metastasis is complex. For example, inhibiting ACCs will increase Acytl-CoA levels, and this may lead to the suppression of ACC1 stimulated breast cancer metastasis28. Some cancers that metastasize to the brain will select lipid-poor regions as these cancer cells can make their own lipids; thus, targeting FAS was effective at preventing the survival of breast cancer cells that have metastasized to the brain29. In general, cancer cells are characterized by elevated lipid metabolism, which is controlled by rate-limiting lipogenic enzymes. Unfortunately, healthy cells need lipids too, so the goal is to slow, not stop the activity of these essential enzymes, and doing so tends to slow the growth of cancers. Inhibiting changes in lipid metabolism through small molecule inhibitors has emerged as a promising area of cancer research2.
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Svensson RU, Parker SJ, Eichner LJ, et al. 2016. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat. Med. 22, 1108-1119
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Alwarawrah Y, Hughes P, Loiselle D, et al. 2016. Fasnall, a selective FASN inhibitor, shows potent anti-tumor activity in the MMTV-Neu model of HER2+ breast cancer. Cell Chem. Biol. 23,678-688
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Pinkosky SL, Newton RS, Day EA, et al. 2016. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat. Commun. 7, 13457
Zhou Y, Tao J, Calvisi DF, Chen X. 2022. Role of Lipogenesis Rewiring in Hepatocellular Carcinoma. Semin Liver Dis. 42(1),77-86. doi: 10.1055/s-0041-1731709.
Zhao S, Jang C, Liu J, et al. 2020. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature. 579, 586-591
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