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

Bonagas, N. ; Scaletti, E.R. LU ; Stenmark, P. LU orcid and Helleday, T. (2022) In Nature Cancer 3(2). p.156-172
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... (More)
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. © 2022, The Author(s). (Less)
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Contribution to journal
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keywords
enzyme, enzyme inhibitor, LY345899, methylenetetrahydrofolate dehydrogenase/cyclohydrolase, resazurin, small interfering RNA, TH7299, TH9028, TH9619, thymidine, unclassified drug, uracil, acute myeloid leukemia, apoptosis assay, Article, cancer growth, cell culture, cell cycle assay, cell viability assay, chemical structure, colony formation, comet assay, confocal microscopy, crystal structure, crystallography, DNA damage, DNA replication, EC50, flow cytometry, gene knockdown, genomic instability, high throughput screening, human, human cell, IC50, physical chemistry, plasmid, RNA interference, S phase cell cycle checkpoint, surface plasmon resonance, tumor metabolism, Western blotting
in
Nature Cancer
volume
3
issue
2
pages
17 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85125665402
  • pmid:35228749
ISSN
2662-1347
DOI
10.1038/s43018-022-00331-y
language
English
LU publication?
yes
id
7e0eea0f-45be-41ba-8a0e-cc9ce8ca6504
date added to LUP
2022-08-02 10:56:14
date last changed
2024-02-13 09:13:02
@article{7e0eea0f-45be-41ba-8a0e-cc9ce8ca6504,
  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. © 2022, The Author(s).}},
  author       = {{Bonagas, N. and Scaletti, E.R. and Stenmark, P. and Helleday, T.}},
  issn         = {{2662-1347}},
  keywords     = {{enzyme; enzyme inhibitor; LY345899; methylenetetrahydrofolate dehydrogenase/cyclohydrolase; resazurin; small interfering RNA; TH7299; TH9028; TH9619; thymidine; unclassified drug; uracil; acute myeloid leukemia; apoptosis assay; Article; cancer growth; cell culture; cell cycle assay; cell viability assay; chemical structure; colony formation; comet assay; confocal microscopy; crystal structure; crystallography; DNA damage; DNA replication; EC50; flow cytometry; gene knockdown; genomic instability; high throughput screening; human; human cell; IC50; physical chemistry; plasmid; RNA interference; S phase cell cycle checkpoint; surface plasmon resonance; tumor metabolism; Western blotting}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{156--172}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Cancer}},
  title        = {{Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress}},
  url          = {{http://dx.doi.org/10.1038/s43018-022-00331-y}},
  doi          = {{10.1038/s43018-022-00331-y}},
  volume       = {{3}},
  year         = {{2022}},
}