Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and laboratory study without human participants
PubMed 38997257 · doi:10.1038/s41467-024-50157-8
What was done
Genetically engineered mouse models of lung cancer bearing Kras G12D/+; Lkb1-/- (KL) or Kras G12D/+; P53-/- (KP) mutations were used to evaluate the consequences of G6PD ablation on tumorigenesis. In vivo stable isotope tracing and metabolomics were performed to assess NADPH production, redox homeostasis, and de novo lipogenesis. Tumor-derived cell lines were also examined for downstream metabolic adaptations and sensitivity to serine and glycine depletion.
What was found
No quantitative effect sizes or statistical values are reported in the abstract. G6PD ablation significantly suppressed lung tumor growth in KL mice but had no such effect in KP mice. In KL tumors, G6PD loss impaired NADPH generation, disrupted redox balance, inhibited lipogenesis, and triggered p53 activation. Advanced G6PD-deficient KL tumors compensated by upregulating serine-driven one-carbon metabolism, making tumor-derived cell lines sensitive to serine/glycine deprivation.
Why it matters
The findings demonstrate that specific co-occurring oncogenic mutations dictate metabolic reliance on the pentose phosphate pathway. This highlights G6PD inhibition, alone or alongside serine/glycine pathway disruption, as a potential strategy for KRAS/LKB1 co-mutated lung cancers.
Limits
The abstract lacks specific quantitative measurements, confidence intervals, and animal sample numbers. Findings are limited to preclinical murine and cell-line models and have not been evaluated in human clinical settings.
Cited by
- supports NADPH is utilized by cells to direct electrons to form carbon-carbon bonds and convert ribonucleotides into deoxyribonucleotides.