Inhibiting the Rate-Limiting Lipogenic Enzymes that Characterize Cancer Cells

Acetyl-CoA carboxylases

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 isoforms^7,8. 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 treatments^8,9. 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

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.

Stearoyl-CoA desaturase

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 balance^23,24. 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.