Journal Article

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

Chalkiadaki, Christina, Loseva, Olga, Bonagas, Nadilly, Sørensen, Claus Storgaard, Meiser, Johannes, Long, Maeve, Hodek, Ondřej, Eiden, Kim, Borhade, Sanjay, Homan, Evert, Paggetti, Jérôme, Helleday, Thomas, Marttila, Petra, Green, Alanna C., Bernardin, François, Lesur, Antoine, Ghahe, Elahe Kamali, Slipicevic, Ana, Jiménez-Alonso, Julio J., Sandberg, Lars, Viry, Elodie, Frödin, Morten, Ramos, Louise, Cookson, Victoria, Wiita, Elisée, Letellier, Elisabeth, Jemth, Ann-Sofie, Henriksson, Martin, Johansson, Annika I., Meyers, Marianne, Kiweler, Nicole, Moussay, Etienne, Mortusewicz, Oliver, Vallin, Karl S. A.

2023

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/58 / 13/31 / 631/443/319 / 631/67/2327 / 631/80/82 / Biomedical and Life Sciences / Cancer / Carbon / Cell and Molecular Biology / Cell cycle / Cell death / Cell- och molekylärbiologi / CRISPR / Dehydrogenases / Dihydrofolate reductase / Enzymes / Folic acid / Folic Acid - metabolism / Formates / Hypoxanthine / Life Sciences / Metabolism / Methylenetetrahydrofolate dehydrogenase / Methylenetetrahydrofolate Dehydrogenase (NADP) - genetics / Methylenetetrahydrofolate Dehydrogenase (NADP) - metabolism / Mitochondria / Neoplasms / Purines / Tetrahydrofolates / Tetrahydrofolic acid / Toxicity / Trapping / Variance analysis / Vitamin B