Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer.
Nat Commun
; 15(1): 5857, 2024 Jul 12.
Article
in En
| MEDLINE
| ID: mdl-38997257
ABSTRACT
Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NADPH production route is the oxidative pentose phosphate pathway (committed step glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer mouse models, we show that G6PD ablation significantly suppresses KrasG12D/+;Lkb1-/- (KL) but not KrasG12D/+;P53-/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics reveal that G6PD ablation significantly impairs NADPH generation, redox balance, and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation activates p53, suppressing tumor growth. As tumors progress, G6PD-deficient KL tumors increase an alternative NADPH source from serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oxidation-Reduction
/
Proto-Oncogene Proteins p21(ras)
/
Protein Serine-Threonine Kinases
/
Glucosephosphate Dehydrogenase
/
Homeostasis
/
Lung Neoplasms
/
NADP
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Nat Commun
Journal subject:
BIOLOGIA
/
CIENCIA
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Reino Unido