The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies.
Animals
Clustered Regularly Interspaced Short Palindromic Repeats
Drug Resistance, Neoplasm
Folic Acid
/ metabolism
Humans
Male
Methylenetetrahydrofolate Reductase (NADPH2)
/ metabolism
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Molecular Targeted Therapy
Neoplasms
/ drug therapy
Proto-Oncogene Proteins c-myc
/ biosynthesis
U937 Cells
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
18
08
2019
revised:
02
07
2020
accepted:
18
08
2020
pubmed:
23
8
2020
medline:
25
11
2021
entrez:
23
8
2020
Statut:
ppublish
Résumé
Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid-related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme MTHFR, which exhibits reduced-function polymorphisms in about 10% of Caucasians, induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Furthermore, this effect is abrogated by supplementation with the MTHFR enzymatic product CH
Identifiants
pubmed: 32826232
pii: 2159-8290.CD-19-0970
doi: 10.1158/2159-8290.CD-19-0970
pmc: PMC8044910
mid: NIHMS1651496
doi:
Substances chimiques
MYC protein, human
0
Proto-Oncogene Proteins c-myc
0
Folic Acid
935E97BOY8
MTHFR protein, human
EC 1.5.1.20
MTHFR protein, mouse
EC 1.5.1.20
Methylenetetrahydrofolate Reductase (NADPH2)
EC 1.5.1.20
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1894-1911Subventions
Organisme : NCI NIH HHS
ID : R35 CA210030
Pays : United States
Organisme : European Research Council
ID : 758848
Pays : International
Organisme : NCI NIH HHS
ID : R01 CA207083
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007171
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA222684
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2020 American Association for Cancer Research.
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