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

Author:

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

Abstract

AbstractThe 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.

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology

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