Kerr Emma M, Gaude Edoardo, Turrell Frances K, Frezza Christian, Martins Carla P
MRC Cancer Unit, University of Cambridge, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.
Nature. 2016 Mar 3;531(7592):110-3. doi: 10.1038/nature16967. Epub 2016 Feb 24.
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.
RAS/丝裂原活化蛋白激酶（MAPK）信号通路在非小细胞肺癌中经常失调，通常是通过KRAS激活突变。单个内源性突变Kras等位基因足以促进小鼠肺肿瘤形成，但恶性进展需要额外的基因改变。我们最近发现，来自Kras(G12D/+);p53基因缺失小鼠的晚期肺肿瘤经常表现出Kras(G12D)等位基因富集（Kras(G12D)/Kras(野生型)>1）（参考文献7），这意味着在进展过程中突变Kras拷贝数增加是被正向选择的。在这里，我们通过对突变Kras纯合子和杂合子小鼠胚胎成纤维细胞及肺癌细胞的全面分析表明，这些基因型在表型上是不同的。特别是，Kras(G12D/G12D)细胞表现出糖酵解转换，伴随着葡萄糖衍生代谢物进入三羧酸循环和谷胱甘肽生物合成的通道增加，从而导致谷胱甘肽介导的解毒增强。这种代谢重编程在突变KRAS纯合子非小细胞肺癌细胞中以及在体内自发的晚期小鼠肺肿瘤（其显示出高频率的Kras(G12D)拷贝数增加）中得以重现，但在相应的早期肿瘤（Kras(G12D)杂合子）中则未出现。最后，我们证明突变Kras拷贝数增加产生了独特的代谢依赖性，可被利用来选择性地靶向这些侵袭性突变Kras肿瘤。我们的数据表明，突变Kras肺肿瘤不是单一疾病，而是一个异质性群体，由两类具有不同代谢谱、预后和治疗敏感性的肿瘤组成，可根据其相对突变等位基因含量进行区分。据我们所知，我们还首次提供了肺癌恶性进展过程中代谢重编程的体内证据。
