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Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities.
- Source :
-
Nature [Nature] 2016 Mar 03; Vol. 531 (7592), pp. 110-3. Date of Electronic Publication: 2016 Feb 24. - Publication Year :
- 2016
-
Abstract
- The RAS/MAPK (mitogen-activated protein kinase) signalling pathway is frequently deregulated in non-small-cell lung cancer, often through KRAS activating mutations. A single endogenous mutant Kras allele is sufficient to promote lung tumour formation in mice but malignant progression requires additional genetic alterations. We recently showed that advanced lung tumours from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) allelic enrichment (Kras(G12D)/Kras(wild-type) > 1) (ref. 7), implying that mutant Kras copy gains are positively selected during progression. Here we show, through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channelling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous non-small-cell lung cancer cells and in vivo, in spontaneous advanced murine lung tumours (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumours (Kras(G12D) heterozygous). Finally, we demonstrate that mutant Kras copy gain creates unique metabolic dependences that can be exploited to selectively target these aggressive mutant Kras tumours. Our data demonstrate that mutant Kras lung tumours are not a single disease but rather a heterogeneous group comprising two classes of tumours with distinct metabolic profiles, prognosis and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. We also provide the first, to our knowledge, in vivo evidence of metabolic rewiring during lung cancer malignant progression.
- Subjects :
- Alleles
Animals
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung metabolism
Carcinoma, Non-Small-Cell Lung pathology
Cell Line, Tumor
Cell Transformation, Neoplastic drug effects
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic metabolism
Cell Transformation, Neoplastic pathology
Citric Acid Cycle
Disease Progression
Female
Fibroblasts metabolism
Genotype
Glutathione biosynthesis
Glutathione metabolism
Lung Neoplasms genetics
Lung Neoplasms pathology
Male
Mice
Oxidation-Reduction
Phenotype
Prognosis
DNA Copy Number Variations genetics
Genes, ras genetics
Glucose metabolism
Glycolysis
Lung Neoplasms drug therapy
Lung Neoplasms metabolism
Mutation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 531
- Issue :
- 7592
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 26909577
- Full Text :
- https://doi.org/10.1038/nature16967