Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities
Pedro Martins, Carla
Nature Publishing Group
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Kerr, E., Gaude, E., Turrell, F., Frezza, C., & Pedro Martins, C. (2016). Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities. Nature, 531 110-113. https://doi.org/10.1038/nature16967
The RAS/MAPK-signalling pathway is frequently deregulated in non-small cell lung cancer (NSCLC), often through KRAS activating mutations[1-3]. A single endogenous mutant Kras allele is sufficient to promote lung tumour formation in mice but malignant progression requires additional genetic alterations[4-7]. 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), implying that mutant Kras copy gains are positively selected during progression. Through a comprehensive analysis of mutant Kras homozygous and heterozygous MEFs and lung cancer cells we now show 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 TCA cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous NSCLC 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 comprised of two classes of tumours with distinct metabolic profiles, prognosis and therapeutic susceptibility, which can be discriminated based on their relative mutant allelic content. We also provide the first in vivo evidence of metabolic rewiring during lung cancer malignant progression.
We thank T. Jacks (Kras^LSL-G12D), A. Berns (p53^Fx) and the NIH Mouse repository for mice. We also thank Sam Kleeman and Patricia Ogger for assistance with redox cell profiling and cell viability assays, respectively. We are very thankful to CRUK CI BRU staff for support with in vivo work and all the members of the Martins lab for critical comments and advice. This work was supported by the Medical Research Council.
Medical Research Council (MC_UU_12022/6)
Medical Research Council (MC_UU_12022/4)
MRC (MC_UU_12022/1_do not transfer?)
External DOI: https://doi.org/10.1038/nature16967
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253795