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

Robert U. Svensson, Seth J. Parker, Lillian J. Eichner, Matthew J. Kolar, Martina Wallace, Sonja N. Brun, Portia S. Lombardo, Jeanine L. Van Nostrand, Amanda Hutchins, Lilliana Vera, Laurie Gerken, Jeremy Greenwood, Sathesh Bhat, Geraldine Harriman, William F. Westlin, H. James Harwood, Alan Saghatelian, Rosana Kapeller, Christian M. Metallo, Reuben J. Shaw*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

392 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1108-1119
Number of pages12
JournalNature Medicine
Volume22
Issue number10
DOIs
StatePublished - Oct 1 2016

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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