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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.

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Figure 1: Acetyl-CoA carboxylase 1 is required for FASyn to support viability of non-small-cell lung cancer cells in vitro and in vivo.
Figure 2: Properties of ND-646, a small-molecule allosteric inhibitor of ACC.
Figure 3: ND-646 inhibits FASyn in vitro and induces apoptosis in NSCLC cells.
Figure 4: ND-646 inhibits FASyn and tumor growth in NSCLC xenograft models.
Figure 5: ND-646 inhibits FASyn in lung tumors of KrasG12D;Trp53−/− and KrasG12D;Stk11−/− mouse models of NSCLC and lowers plasma free fatty acids.
Figure 6: ND-646 suppresses KrasG12D;Trp53−/− and KrasG12D;Stk11−/− autochthonous NSCLC tumor growth.

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Acknowledgements

This study was supported by grants from the US National Institutes of Health (NIH) (grant no. R01CA172229 (R.J.S.), P01CA120964 (R.J.S.) and R01CA188652 (C.M.M.)), the Samuel Waxman Cancer Research Foundation (R.J.S.), The Leona M. and Harry B. Helmsley Charitable Trust (grant no. 2012-PG- MED002; R.J.S.) and the US Department of Defense (grant no. W81-XWH-13-1-01-5; C.M.M. and R.J.S.). R.U.S. was supported by a postdoctoral fellowship from the American Cancer Society (ACS#124183-PF-13-023-01-CSM). L.J.E. was supported by a T32 postdoctoral training grant to the Salk Institute Cancer Center (5 T32 CA009370) and a postdoctoral fellowship from the American Cancer Society (PF-15-037-01-DMC). S.J.P. was supported by an F31 NIH predoctoral training fellowship (F31CA196066-01). M.J.K. is supported by a UCSD Medical Scientist Training Program fellowship (2 T32 GM007198). P.S.L. was supported by a T32 predoctoral training grant (T32 GM 007240). S.N.B. is supported by a T32 postdoctoral training grant to the Salk Institute Cancer Center (T32: 5T32CA009370-33). J.L.V.N. is supported by a Damon Runyon Cancer Research Foundation fellowship (DRG-2219-15). We thank K. McIntyre and the histology core at the Salk Institute, which is also supported in part through the Salk CCSG P30 CA014195 grant, as well as the next-generation sequencing (NGS) core facility at the Salk Institute, which is supported with funding from the NIH–NCI CCSG P30 014195 grant, the Chapman Foundation, the Glenn Foundation and the Helmsley Charitable Trust. We also thank R. Farid for Figure 2b, E. Smith for Figure 2j, G. Wahl for the p53-specific antibody used in the IHC experiments and P. Hollstein for technical assistance.

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R.U.S. and R.J.S. designed the experiments and wrote the manuscript with input from all authors; R.U.S. performed all experiments, except as noted; P.S.L. and J.L.V.N. assisted with the CRISPR–Cas9 studies in Figure 1; S.J.P. and C.M.M. performed the FASyn analysis (Figs. 1 and 3) and, with help from M.W., analyzed FASyn in the tumors prepared by R.U.S. in Figure 5; M.J.K. and A.S. performed the FFA analysis for Figures 5 and 6; L.J.E. performed the IHC and tumor-burden analysis in Figures 4 and 6; S.N.B., L.V., L.G. and A.H. assisted with dosing in the in vivo experiments in Figures 4 and 6; G.H., W.F.W., J.G., S.B., H.J.H. and R.K. discovered and developed the series of ACC inhibitors that contains ND-646 and ND-608, conducted the enzyme inhibition and pharmacokinetic characterization of both compounds, and conducted the molecular modeling studies (Fig. 2b,i).

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Correspondence to Rosana Kapeller or Reuben J Shaw.

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J.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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Svensson, R., Parker, S., Eichner, L. et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med 22, 1108–1119 (2016). https://doi.org/10.1038/nm.4181

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