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Nat Med. 2016 Oct;22(10):1108-1119. doi: 10.1038/nm.4181. Epub 2016 Sep 19.

Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.

Author information

1
Department of Molecular and Cell Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
2
Department of Bioengineering, University of California San Diego, La Jolla, California, USA.
3
Clayton Foundation Laboratories of Peptide Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
4
Schrödinger, New York, New York, USA.
5
Nimbus Therapeutics, Cambridge, Massachusetts, USA.
6
Moores Cancer Center, University of California San Diego, La Jolla, California, USA.

Abstract

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.

PMID:
27643638
PMCID:
PMC5053891
DOI:
10.1038/nm.4181
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

COMPETING FINANCIAL INTERESTSJ.G. and S.B. are employed by Schrödinger; G.H., W.F.W., H.J.H., and R.K. are employed by Nimbus Therapeutics.

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