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Search: WFRF:(Cookson Victoria)

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1.
  • Bonagas, Nadilly, et al. (author)
  • Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
  • 2022
  • In: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
  • Journal article (peer-reviewed)abstract
    • The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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2.
  • Green, Alanna C., et al. (author)
  • Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
  • 2023
  • In: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 5:4, s. 642-659
  • Journal article (peer-reviewed)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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  • Result 1-2 of 2
Type of publication
journal article (2)
Type of content
peer-reviewed (2)
Author/Editor
Henriksson, Martin (2)
Helleday, Thomas (2)
Loseva, Olga (2)
Bonagas, Nadilly (2)
Marttila, Petra (2)
Wiita, Elisee (2)
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Borhade, Sanjay (2)
Green, Alanna C. (2)
Jemth, Ann-Sofie (2)
Cookson, Victoria (2)
Kiweler, Nicole (2)
Sandberg, Lars (2)
Arvidsson, Per I. (1)
Eriksson, Anders (1)
Abdurakhmanov, Eldar ... (1)
Svensson, Richard (1)
Knapp, Stefan (1)
Haraldsson, Martin (1)
Garg, Neeraj (1)
Krokan, Hans E (1)
Jarvius, Malin (1)
Parrow, Vendela (1)
Stenmark, Pål (1)
Bengtsson, Christoff ... (1)
Liu, Jianping (1)
Wannberg, Johan (1)
Martens, Ulf (1)
Häggblad, Maria (1)
Sörensen, Claus Stor ... (1)
Vallin, Karl (1)
Karsten, Stella (1)
Pham, Therese (1)
Scobie, Martin (1)
Berglund, Ulrika War ... (1)
Gustafsson, Nina M. ... (1)
Gustafsson, Robert, ... (1)
Vallin, Karl S. A. (1)
Sarno, Antonio (1)
Gokturk, Camilla (1)
Rasti, Azita (1)
Unterlass, Judith E. (1)
Andersson, Yasmin (1)
Scaletti, Emma R. (1)
Sanjiv, Kumar (1)
Pudelko, Linda (1)
Kunz, Ben (1)
Desroses, Matthieu (1)
Iliev, Petar (1)
Färnegårdh, Katarina (1)
Kramer, Andreas (1)
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University
Stockholm University (2)
Karolinska Institutet (2)
Umeå University (1)
Royal Institute of Technology (1)
Uppsala University (1)
Lund University (1)
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RISE (1)
Swedish University of Agricultural Sciences (1)
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Language
English (2)
Research subject (UKÄ/SCB)
Natural sciences (2)
Medical and Health Sciences (2)

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