Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress

Nadilly Bonagas, Nina M.S. Gustafsson, Martin Henriksson, Petra Marttila, Robert Gustafsson, Elisée Wiita, Sanjay Borhade, Alanna C. Green, Karl S.A. Vallin, Antonio Sarno, Richard Svensson, Camilla Göktürk, Therese Pham, Ann Sofie Jemth, Olga Loseva, Victoria Cookson, Nicole Kiweler, Lars Sandberg, Azita Rasti, Judith E. UnterlassMartin Haraldsson, Yasmin Andersson, Emma R. Scaletti, Christoffer Bengtsson, Cynthia B.J. Paulin, Kumar Sanjiv, Eldar Abdurakhmanov, Linda Pudelko, Ben Kunz, Matthieu Desroses, Petar Iliev, Katarina Färnegårdh, Andreas Krämer, Neeraj Garg, Maurice Michel, Sara Häggblad, Malin Jarvius, Christina Kalderén, Amanda Bögedahl Jensen, Ingrid Almlöf, Stella Karsten, Si Min Zhang, Maria Häggblad, Anders Eriksson, Jianping Liu, Björn Glinghammar, Natalia Nekhotiaeva, Fredrik Klingegård, Tobias Koolmeister, Ulf Martens, Sabin Llona-Minguez, Ruth Moulson, Helena Nordström, Vendela Parrow, Leif Dahllund, Birger Sjöberg, Irene L. Vargas, Duy Duc Vo, Johan Wannberg, Stefan Knapp, Hans E. Krokan, Per I. Arvidsson, Martin Scobie, Johannes Meiser, Pål Stenmark, Ulrika Warpman Berglund, Evert J. Homan, Thomas Helleday*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)156-172
Number of pages17
JournalNature Cancer
Volume3
Issue number2
DOIs
Publication statusPublished - Feb 2022

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