2. Academic Validation
  3. Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells

  • Nat Metab. 2023 Apr;5(4):642-659. doi: 10.1038/s42255-023-00771-5.
Alanna C Green # 1,  Petra Marttila # 2,  Nicole Kiweler # 3,  Christina Chalkiadaki 2,  Elisée Wiita 2,  Victoria Cookson 1,  Antoine Lesur 3,  Kim Eiden 3,  François Bernardin 3,  Karl S A Vallin 2 4,  Sanjay Borhade 2 5,  Maeve Long 2,  Elahe Kamali Ghahe 6,  Julio J Jiménez-Alonso 2 7,  Ann-Sofie Jemth 2,  Olga Loseva 2,  Oliver Mortusewicz 2,  Marianne Meyers 8,  Elodie Viry 9,  Annika I Johansson 10,  Ondřej Hodek 11,  Evert Homan 2,  Nadilly Bonagas 2,  Louise Ramos 1,  Lars Sandberg 12,  Morten Frödin 6,  Etienne Moussay 9,  Ana Slipicevic 2 13,  Elisabeth Letellier 8,  Jérôme Paggetti 9,  Claus Storgaard Sørensen 6,  Thomas Helleday 14 15,  Martin Henriksson 16,  Johannes Meiser 17
Affiliations

Affiliations

  • 1 Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK.
  • 2 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
  • 3 Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
  • 4 RISE Research Institutes of Sweden, Södertälje, Sweden.
  • 5 RedGlead Discover, Lund, Sweden.
  • 6 Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
  • 7 Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain.
  • 8 Faculty of Science, Technology and Medicine, Department of Life Sciences and Medicine, Molecular Disease Mechanisms Group, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
  • 9 Tumor Stroma Interactions, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
  • 10 Swedish Metabolomics Centre, Department of Plant Physiology, Umeå University, Umeå, Sweden.
  • 11 Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, Umeå, Sweden.
  • 12 Drug Discovery and Development Platform, Science for Life Laboratory, Department of Organic Chemistry, Stockholm University, Solna, Sweden.
  • 13 One-carbon Therapeutics AB, Stockholm, Sweden.
  • 14 Weston Park Cancer Centre and Mellanby Centre for Musculoskeletal Research, Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK. thomas.helleday@scilifelab.se.
  • 15 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden. thomas.helleday@scilifelab.se.
  • 16 Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden. martin.henriksson@scilifelab.se.
  • 17 Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg. Johannes.Meiser@lih.lu.
  • # Contributed equally.
PMID: 37012496 DOI: 10.1038/s42255-023-00771-5
Abstract

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.

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