Targeting ACSS2 with a Transition-State Mimetic Inhibits Triple-Negative Breast Cancer Growth

Cancer Res. 2021 Mar 1;81(5):1252-1264. doi: 10.1158/0008-5472.CAN-20-1847. Epub 2021 Jan 7.


Acetyl-CoA is a vitally important and versatile metabolite used for many cellular processes including fatty acid synthesis, ATP production, and protein acetylation. Recent studies have shown that cancer cells upregulate acetyl-CoA synthetase 2 (ACSS2), an enzyme that converts acetate to acetyl-CoA, in response to stresses such as low nutrient availability and hypoxia. Stressed cancer cells use ACSS2 as a means to exploit acetate as an alternative nutrient source. Genetic depletion of ACSS2 in tumors inhibits the growth of a wide variety of cancers. However, there are no studies on the use of an ACSS2 inhibitor to block tumor growth. In this study, we synthesized a small-molecule inhibitor that acts as a transition-state mimetic to block ACSS2 activity in vitro and in vivo. Pharmacologic inhibition of ACSS2 as a single agent impaired breast tumor growth. Collectively, our findings suggest that targeting ACSS2 may be an effective therapeutic approach for the treatment of patients with breast cancer. SIGNIFICANCE: These findings suggest that targeting acetate metabolism through ACSS2 inhibitors has the potential to safely and effectively treat a wide range of patients with cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetate-CoA Ligase / antagonists & inhibitors*
  • Acetate-CoA Ligase / genetics
  • Acetate-CoA Ligase / metabolism
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor / methods
  • Drug Stability
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Fatty Acids / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • HEK293 Cells
  • Humans
  • Mice, Inbred Strains
  • Molecular Docking Simulation
  • Molecular Targeted Therapy / methods
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Fatty Acids
  • ACSS2 protein, human
  • Acetate-CoA Ligase