4.8 Article

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

Journal

NATURE METABOLISM
Volume 5, Issue 4, Pages 642-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s42255-023-00771-5

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Cancer cells upregulate 1C metabolism to meet their increased need for nucleotides. TH9619 selectively kills cancer cells by targeting nuclear MTHFD2 but not inhibiting mitochondrial MTHFD2. This leads to the accumulation of 10-formyl-tetrahydrofolate and thymidylate depletion, resulting in the death of MTHFD2-expressing cancer cells. This study uncovers a new folate trapping mechanism and provides insights into targeting cancer through 1C metabolism.
Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism. In this study, Green, Marttila, Kiweler et al. characterize one-carbon metabolism rewiring in response to a dual MTHFD1 and MTHFD2 inhibitor. This work provides insight into one-carbon fluxes, and reveals a previously uncharacterized vulnerability in cancer cells created by folate trapping.

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