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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..ORCID iD: 0000-0001-7336-4065
Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
Karolinska Inst, Dept Oncol Pathol, Sci Life Lab, Solna, Sweden..
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2022 (English)In: NATURE CANCER, ISSN 2662-1347, Vol. 3, no 2, p. 156-Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2022. Vol. 3, no 2, p. 156-
National Category
Cancer and Oncology Cell Biology
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URN: urn:nbn:se:uu:diva-470347DOI: 10.1038/s43018-022-00331-yISI: 000762300200004PubMedID: 35228749OAI: oai:DiVA.org:uu-470347DiVA, id: diva2:1646786
Funder
EU, FP7, Seventh Framework Programme, 115489Swedish Research Council, 2015-00162Swedish Research Council, 2017-06095Swedish Research Council, 2018-03406EU, European Research Council, TAROX-695376Swedish Cancer Society, CAN 2018/600Swedish Cancer Society, 201287 PjFAvailable from: 2022-03-24 Created: 2022-03-24 Last updated: 2022-03-24Bibliographically approved

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Svensson, RichardAbdurakhmanov, EldarJarvius, MalinNordström, HelenaParrow, VendelaWannberg, Johan

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Bonagas, NadillySvensson, RichardAbdurakhmanov, EldarKramer, AndreasJarvius, MalinNordström, HelenaParrow, VendelaWannberg, Johan
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Department of PharmacyScience for Life Laboratory, SciLifeLabBiochemistryCancer Pharmacology and Computational MedicinePreparative Medicinal Chemistry
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