Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models
Open accessAbstract
Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology.
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The ACC allosteric inhibitor ND-646 has antitumor efficacy in autochthonous mouse lung tumor models.
“Genetic knockdown of ACC induces apoptosis in cancer cell lines (Brusselmans et al., 2005; Chajes et al., 2006), and an allosteric inhibitor of ACC, ND-646, has shown antitumor efficacy in autochthonous mouse lung tumor models (Svensson et al., 2016).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Svensson et al., 2016
Targeting ACC to limit fatty acid synthesis can suppress lung tumor progression in some models, but loss of ACC activity can accelerate tumor growth in other cancer models.
“For example, while targeting ACC to limit fatty synthesis can suppress lung tumor progression in some models (Svensson et al., 2016), loss of ACC activity can accelerate tumor growth in other cancer models (Jeon et al., 2012).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Svensson et al., 2016
PHD3 is suppressed in cancers that rely on FAO, such as AML and prostate cancer, and elevated in cancers that rely on FAS such as breast and non-small-lung-cell cancer.
“PHD3 is suppressed in cancers that rely on FAO, such as AML and prostate cancer, and elevated in cancers that rely on FAS such as breast and non-small-lung-cell cancer.55–57”
From The multifaceted contributions of mitochondria to cellular metabolism (2018) · cites this paper as [57]
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“Similarly, LKB1-deficient NSCLC cells exhibit enhanced sensitivity to the energetic stress induced by erlotinib in vitro and in vivo [67].”
BackgroundAcetyl-CoA: an interplay between metabolism and epigenetics in cancer
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“Here, we demonstrate that LKB1 regulates JNK stress signaling and the apoptotic response of cancer cells independent of its tumor suppressor activity mediated by AMPK 25 – 27 and SIK 28,29 kinases.”
- Authors
- Svensson, R. U., Parker, S. J., Eichner, L. J., Kolar, M. J., Wallace, M., Brun, S. N., Lombardo, P. S., Van Nostrand, J. L., Hutchins, A., Vera, L., Gerken, L., Greenwood, J., Bhat, S., Harriman, G., Westlin, W. F., Harwood, H. J., Saghatelian, A., Kapeller, R., Metallo, C. M., & Shaw, R. J.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- Schrodinger (United States) (US)
- Corresponding author
- Kapeller, Rosana
- Shaw, Reuben J
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-09-19
- Volume
- 22
- Issue
- 10
- Pages
- 1108-1119
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5053891
- OpenAlex
- W2522492952
- Cited by
- 536
- References
- 42
- Citations by year
- 2026: 52 · 2025: 67 · 2024: 47 · 2023: 54 · 2022: 65 · 2021: 58 · 2020: 58 · 2019: 53 · 2018: 45 · 2017: 33 · 2016: 4
- FWCI
- 18.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Cancer Institute (R01CA172229, R01CA188652, P01CA120964, T32CA009370, P30CA014195, F31CA196066)
- National Institute of General Medical Sciences (T32GM007240, T32GM007198)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- acetyl-CoA carboxylase, allosteric inhibitors, fatty acid synthesis, non-small cell lung cancer, tumor growth, cancer metabolism, acetyl-CoA carboxylase 1, acetyl-CoA carboxylase 2, KRAS, Trp53, STK11, genetically engineered mouse models, xenografts, metabolic vulnerability
- MeSH terms
- Acetyl-CoA Carboxylase, Acetyltransferases, Allosteric Regulation, Animals, Carcinoma, Non-Small-Cell Lung, Enzyme Inhibitors, Fatty Acids, Humans, Lung Neoplasms, Pyrimidinones, Thiophenes, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Protein Serine-Threonine Kinases, Mice, Knockout, Xenograft Model Antitumor Assays, Cell Proliferation, Lipid Metabolism, Mice, AMP-Activated Protein Kinases, Molecular Targeted Therapy
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