1. Targeting ACSS2 with a Transition-State Mimetic Inhibits Triple-Negative Breast Cancer Growth
- Author
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Andrew V. Kossenkov, Joshua D. Shaffer, Katherine Pniewski, Caroline Perry, Zachary T. Schug, Katelyn D. Miller, Joseph M. Salvino, Emmanuel Skordalakes, Sara B. Papp, Jessica C. Casciano, Yellamelli V.V. Srikanth, Joel Cassel, Jesse N Velasco-Silva, and Tomas M. Aramburu
- Subjects
0301 basic medicine ,Cancer Research ,Acetate-CoA Ligase ,Antineoplastic Agents ,Mice, Inbred Strains ,Triple Negative Breast Neoplasms ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Breast cancer ,Downregulation and upregulation ,Drug Stability ,In vivo ,Cell Line, Tumor ,ACSS2 ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Enzyme Inhibitors ,Triple-negative breast cancer ,Fatty acid synthesis ,Chemistry ,Fatty Acids ,medicine.disease ,Xenograft Model Antitumor Assays ,In vitro ,Gene Expression Regulation, Neoplastic ,Molecular Docking Simulation ,030104 developmental biology ,HEK293 Cells ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Female ,Drug Screening Assays, Antitumor - Abstract
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.
- Published
- 2020