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

DOI: 10.1038/s43018-022-00331-y DOI Help

Authors: Nadilly Bonagas (Karolinska Institutet) , Nina M. S. Gustafsson (Karolinska Institutet) , Martin Henriksson (Karolinska Institutet) , Petra Marttila (Karolinska Institutet) , Robert Gustafsson (Stockholm University) , Elisée Wiita (Karolinska Institutet) , Sanjay Borhade (Karolinska Institutet) , Alanna C. Green (University of Sheffield) , Karl S. A. Vallin (Karolinska Institutet) , Antonio Sarno (Norwegian University of Science and Technology) , Richard Svensson (Uppsala University) , Camilla Göktürk (Karolinska Institutet) , Therese Pham (Karolinska Institutet) , Ann-Sofie Jemth (Karolinska Institutet) , Olga Loseva (Karolinska Institutet) , Victoria Cookson (University of Sheffield) , Nicole Kiweler (Luxembourg Institute of Health) , Lars Sandberg (Stockholm University) , Azita Rasti (Karolinska Institutet) , Judith E. Unterlass (Karolinska Institutet) , Martin Haraldsson (Karolinska Institutet) , Yasmin Andersson (Royal Institute of Technology (Sweden)) , Emma R. Scaletti (Stockholm University; Lund University) , Christoffer Bengtsson (Stockholm University) , Cynthia B. J. Paulin (Karolinska Institutet) , Kumar Sanjiv (Karolinska Institutet) , Eldar Abdurakhmanov (Uppsala University) , Linda Pudelko (Karolinska Institutet) , Ben Kunz (Karolinska Institutet) , Matthieu Desroses (Karolinska Institutet) , Petar Iliev (Karolinska Institutet) , Katarina Färnegårdh (Stockholm University) , Andreas Krämer (Goethe University) , Neeraj Garg (Uppsala University) , Maurice Michel (Karolinska Institutet) , Sara Häggblad (Stockholm University) , Malin Jarvius (Uppsala University) , Christina Kalderén (Karolinska Institutet) , Amanda Bögedahl Jensen (Karolinska Institutet) , Ingrid Almlöf (Karolinska Institutet) , Stella Karsten (Karolinska Institutet) , Si Min Zhang (Karolinska Institutet) , Maria Häggblad (Stockholm University) , Anders Eriksson (Karolinska Institute) , Jianping Liu (Karolinska Institutet) , Björn Glinghammar (Karolinska Institutet) , Natalia Nekhotiaeva (Karolinska Institutet) , Fredrik Klingegård (Stockholm University) , Tobias Koolmeister (Karolinska Institutet) , Ulf Martens (Stockholm University) , Sabin Llona-Minguez (Karolinska Institutet) , Ruth Moulson (Karolinska Institutet) , Helena Nordström (Uppsala University) , Vendela Parrow (Uppsala University) , Leif Dahllund (Royal Institute of Technology (Sweden)) , Birger Sjöberg (Karolinska Institutet) , Irene L. Vargas (Karolinska Institutet) , Duy Duc Vo (Uppsala University) , Johan Wannberg (Uppsala University) , Stefan Knapp (Goethe University) , Hans E. Krokan (Norwegian University of Science and Technology) , Per I. Arvidsson (Karolinska Institutet) , Martin Scobie (Karolinska Institutet) , Johannes Meiser (Luxembourg Institute of Health) , Pal Stenmark (Stockholm University; Lund University) , Ulrika Warpman Berglund (Karolinska Institutet) , Evert J. Homan (Karolinska Institutet) , Thomas Helleday (Karolinska Institutet; University of Sheffield)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Cancer , VOL 3 , PAGES 156 - 172

State: Published (Approved)
Published: February 2022

Open Access Open Access

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.

Journal Keywords: Cancer; Cancer metabolism; DNA synthesis; Drug discovery; Targeted therapies

Diamond Keywords: Leukaemia

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Other Facilities: PXI at Swiss Light Source

Added On: 04/03/2022 08:41

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)