Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.
Journal
Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
19
03
2021
accepted:
02
05
2022
pubmed:
11
6
2022
medline:
29
7
2022
entrez:
10
6
2022
Statut:
ppublish
Résumé
Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.
Identifiants
pubmed: 35681100
doi: 10.1038/s43018-022-00393-y
pii: 10.1038/s43018-022-00393-y
pmc: PMC9325670
doi:
Substances chimiques
Enzyme Inhibitors
0
Isocitrate Dehydrogenase
EC 1.1.1.41
IDH1 protein, human
EC 1.1.1.42.
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
852-865Subventions
Organisme : NIH HHS
ID : S10 OD030245
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA196643
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA247466
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA150964
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244931
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA227865
Pays : United States
Organisme : NIDDK NIH HHS
ID : R33 DK070291
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA043703
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA248160
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA237421
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA212600
Pays : United States
Informations de copyright
© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
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