Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.
Nat Cancer
; 3(7): 852-865, 2022 07.
Article
en En
| MEDLINE
| ID: mdl-35681100
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Neoplasias Pancreáticas
/
Isocitrato Deshidrogenasa
Tipo de estudio:
Diagnostic_studies
Límite:
Humans
Idioma:
En
Revista:
Nat Cancer
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos