A novel oral inhibitor for one-carbon metabolism and checkpoint kinase 1 inhibitor as a rational combination treatment for breast cancer.

Abstract

Patients with triple-negative breast cancer have a poor prognosis as only a few efficient targeted therapies are available. Cancer cells are characterized by their unregulated proliferation and require large amounts of nucleotides to replicate their DNA. One-carbon metabolism contributes to purine and pyrimidine nucleotide synthesis by supplying one carbon atom. Although mitochondrial one-carbon metabolism has recently been focused on as an important target for cancer treatment, few specific inhibitors have been reported. In this study, we aimed to examine the effects of DS18561882 (DS18), a novel, orally active, specific inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2), a mitochondrial enzyme involved in one-carbon metabolism. Treatment with DS18 led to a marked reduction in cancer-cell proliferation; however, it did not induce cell death. Combinatorial treatment with DS18 and inhibitors of checkpoint kinase 1 (Chk1), an activator of the S phase checkpoint pathway, efficiently induced apoptotic cell death in breast cancer cells and suppressed tumorigenesis in a triple-negative breast cancer patient-derived xenograft model. Mechanistically, MTHFD2 inhibition led to cell cycle arrest and slowed nucleotide synthesis. This finding suggests that DNA replication stress occurs due to nucleotide shortage and that the S-phase checkpoint pathway is activated, leading to cell-cycle arrest. Combinatorial treatment with both inhibitors released cell-cycle arrest, but induced accumulation of DNA double-strand breaks, leading to apoptotic cell death. Collectively, a combination of MTHFD2 and Chk1 inhibitors would be a rational treatment option for patients with triple-negative breast cancer.

• Authors: Jin Lee, Xiaoxi Chen, Yuming Wang, Tatsunori Nishimura, Mengjiao Li, Satoko Ishikawa, Takiko Daikoku, Junya Kawai, Arinobu Tojo, Noriko Gotoh
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 584 Pg. 7-14 (12 20 2021) ISSN: 1090-2104 [Electronic] United States
• PMID: 34753066 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• MTHFD2 protein, human
• Multifunctional Enzymes
• Protein Kinase Inhibitors
• Methylenetetrahydrofolate Dehydrogenase (NADP)
• Checkpoint Kinase 1
• Aminohydrolases

Topics

• Administration, Oral
• Aminohydrolases (antagonists & inhibitors, metabolism)
• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Checkpoint Kinase 1 (antagonists & inhibitors, metabolism)
• Drug Therapy, Combination
• Enzyme Inhibitors (administration & dosage, therapeutic use)
• Female
• Humans
• Methylenetetrahydrofolate Dehydrogenase (NADP) (antagonists & inhibitors, metabolism)
• Mice, Inbred NOD
• Mice, Knockout
• Mice, SCID
• Multifunctional Enzymes (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (therapeutic use)
• S Phase Cell Cycle Checkpoints (drug effects)
• Triple Negative Breast Neoplasms (drug therapy, enzymology, pathology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays (methods)
• Mice