title: Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.
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.
authors.affiliation: Department of Molecular and Cell Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
authors.forename: Robert U
authors.initials: RU
authors.lastname: Svensson
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California, USA.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Parker
authors.affiliation: Department of Molecular and Cell Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
authors.forename: Lillian J
authors.initials: LJ
authors.lastname: Eichner
authors.affiliation: Clayton Foundation Laboratories of Peptide Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Kolar
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Wallace
authors.affiliation: Department of Molecular and Cell Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
authors.forename: Sonja N
authors.initials: SN
authors.lastname: Brun
authors.affiliation: Department of Molecular and Cell Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
authors.forename: Portia S
authors.initials: PS
authors.lastname: Lombardo
authors.affiliation: Department of Molecular and Cell Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
authors.forename: Jeanine L
authors.initials: JL
authors.lastname: Van Nostrand
authors.affiliation: Department of Molecular and Cell Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Hutchins
authors.affiliation: Department of Molecular and Cell Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
authors.forename: Lilliana
authors.initials: L
authors.lastname: Vera
authors.affiliation: Department of Molecular and Cell Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
authors.forename: Laurie
authors.initials: L
authors.lastname: Gerken
authors.affiliation: Schrödinger, New York, New York, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Greenwood
authors.affiliation: Schrödinger, New York, New York, USA.
authors.forename: Sathesh
authors.initials: S
authors.lastname: Bhat
authors.affiliation: Nimbus Therapeutics, Cambridge, Massachusetts, USA.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Harriman
authors.affiliation: Nimbus Therapeutics, Cambridge, Massachusetts, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Westlin
authors.affiliation: Nimbus Therapeutics, Cambridge, Massachusetts, USA.
authors.forename: H James
authors.initials: HJ
authors.lastname: Harwood
authors.affiliation: Clayton Foundation Laboratories of Peptide Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.affiliation: Nimbus Therapeutics, Cambridge, Massachusetts, USA.
authors.forename: Rosana
authors.initials: R
authors.lastname: Kapeller
authors.affiliation: Department of Bioengineering, University of California San Diego, La Jolla, California, USA.|Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
authors.affiliation: Department of Molecular and Cell Biology, Salk Institute for Biological Studies, San Diego, La Jolla, California, USA.
authors.forename: Reuben J
authors.initials: RJ
authors.lastname: Shaw
mesh_terms: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D000494:Allosteric Regulation; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005227:Fatty Acids / Q000096:biosynthesis*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D011744:Pyrimidinones / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D005227:Fatty Acids; C000621677:ND-646; D011744:Pyrimidinones; D013876:Thiophenes; D016159:Tumor Suppressor Protein p53; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); C520105:ACACB protein, human; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase