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Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities

机译：突变的Kras拷贝数定义了代谢重编程和治疗敏感性

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摘要

The RAS/MAPK (mitogen-activated protein kinase) signalling pathway is frequently deregulated in non-small-cell lung cancer, 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 KrasG12D/+; p53-null mice frequently exhibit KrasG12D allelic enrichment (KrasG12D/Kraswild-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, KrasG12D/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 nonsmall- cell lung cancer cells and in vivo, in spontaneous advanced murine lung tumours (which display a high frequency of KrasG12D copy gain), but not in the corresponding early tumours (KrasG12D 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.
机译：非小细胞肺癌中的RAS / MAPK（有丝分裂原激活的蛋白激酶）信号传导通路经常被调节，通常是通过KRAS激活突变（1-3）。一个单一的内源突变型Kras等位基因足以促进小鼠肺肿瘤的形成，但恶性进展还需要其他基因改变（4-7。）我们最近发现，来自KrasG12D / +的晚期肺肿瘤；其发病机制尚不清楚。 p53无效的小鼠经常表现出KrasG12D等位基因富集（KrasG12D / Kraswild型> 1）（参考文献7），这表明突变的Kras复制获得在进展过程中被积极选择。在这里，我们通过对突变的Kras纯合子和杂合子小鼠胚胎成纤维细胞和肺癌细胞进行全面分析，表明这些基因型在表型上是不同的。特别地，KrasG12D / G12D细胞表现出糖酵解转换，与葡萄糖衍生的代谢物进入三羧酸循环和谷胱甘肽生物合成的通道增加有关，导致增强的谷胱甘肽介导的排毒作用。这种代谢重建在突变的KRAS纯合非小细胞肺癌细胞和体内，自发的晚期鼠肺肿瘤（显示出高频率的KrasG12D复制增益）中得以概括，而在相应的早期肿瘤中却没有（KrasG12D杂合）。最后，我们证明了突变的Kras复制增益产生了独特的代谢依赖性，可以利用该依赖性来选择性地靶向这些侵略性的突变Kras肿瘤。我们的数据表明，突变的Kras肺部肿瘤不是单一疾病，而是包括两类肿瘤的异质性组，这两类肿瘤具有不同的代谢谱，预后和治疗敏感性，可根据其相对突变等位基因含量加以区分。就我们所知，我们还提供了肺癌恶性进展过程中代谢重新连接的体内证据。

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  • 来源
    《Nature》 |2016年第7592期|110-113|共4页
  • 作者

    Kerr Emma M.; Gaude Edoardo; Turrell Frances K.; Frezza Christian; Martins Carla P.;

  • 作者单位

    Univ Cambridge, MRC, Canc Unit, Box 197,Cambridge Biomed Campus, Cambridge CB2 0XZ, England;

    Univ Cambridge, MRC, Canc Unit, Box 197,Cambridge Biomed Campus, Cambridge CB2 0XZ, England;

    Univ Cambridge, MRC, Canc Unit, Box 197,Cambridge Biomed Campus, Cambridge CB2 0XZ, England;

    Univ Cambridge, MRC, Canc Unit, Box 197,Cambridge Biomed Campus, Cambridge CB2 0XZ, England;

    Univ Cambridge, MRC, Canc Unit, Box 197,Cambridge Biomed Campus, Cambridge CB2 0XZ, England;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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