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A Braf kinase-inactive mutant induces lung adenocarcinoma

机译：缺乏Braf激酶的突变体诱导肺腺癌

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The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Inactivating BRAF mutants in lung predominate over the activating V600E mutant that is frequently observed in other tumour types(1). Here we demonstrate that the expression of an endogenous Braf(D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis. Moreover, inactivating BRAF mutations have also been identified in a subset of KRAS-driven human lung tumours. Co-expression of Kras(G12V) and Braf(D631A) in mouse lung cells markedly enhances tumour initiation, a phenomenon mediated by Craf kinase activity(2,3), and effectively accelerates tumour progression when activated in advanced lung adenocarcinomas. We also report a key role for the wild-type Braf kinase in sustaining Kras(G12V)/Braf(D631A)-driven tumours. Ablation of the wild-type Braf allele prevents the development of lung adenocarcinoma by inducing a further increase in MAPK signalling that results in oncogenic toxicity; this effect can be abolished by pharmacological inhibition of Mek to restore tumour growth. However, the loss of wild-type Braf also induces transdifferentiation of club cells, which leads to the rapid development of lethal intrabronchiolar lesions. These observations indicate that the signal intensity of the MAPK pathway is a critical determinant not only in tumour development, but also in dictating the nature of the cancer-initiating cell and ultimately the resulting tumour phenotype.
机译：在几乎一半的人类肺腺癌中起始致癌事件仍是未知的，这一事实使选择性靶向疗法的开发复杂化。然而，这些肿瘤具有许多改变而没有明显的致癌功能，包括BRAF失活突变。肺中灭活的BRAF突变体比其他类型的肿瘤中经常观察到的激活的V600E突变体更为重要（1）。在这里，我们证明了小鼠中内源性Braf（D631A）激酶失活同工型的表达（对应于人类BRAF（D594A）突变）在体内触发了肺腺癌，表明BRAF失活突变是肺癌发生中的起始事件。此外，还已经在KRAS驱动的人肺肿瘤的子集中发现了灭活的BRAF突变。在小鼠肺细胞中共表达Kras（G12V）和Braf（D631A）可以显着增强肿瘤的发生，这是由Craf激酶活性介导的现象（2,3），并且在晚期肺腺癌中激活后可以有效地加速肿瘤的进展。我们还报告了野生型Braf激酶在维持Kras（G12V）/ Braf（D631A）驱动的肿瘤中的关键作用。野生型Braf等位基因的切除通过诱导MAPK信号传导进一步增加而导致致癌毒性，从而阻止了肺腺癌的发展；可以通过药理抑制Mek恢复肿瘤生长来消除这种作用。然而，野生型Braf的丢失也诱导了俱乐部细胞的转分化，这导致了致命的细支气管内病变的快速发展。这些观察结果表明，MAPK途径的信号强度不仅在肿瘤发展中而且在决定癌症起始细胞的性质以及最终导致的肿瘤表型方面都是至关重要的决定因素。

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  • 来源
    《Nature》 |2017年第7666期|239-243|共5页
  • 作者

    Nieto Patricia; Ambrogio Chiara; Esteban-Burgos Laura; Gomez-Lopez Gonzalo; Teresa Blasco Maria; Yao Zhan; Marais Richard; Rosen Neal; Chiarle Roberto; Pisano David G.; Barbacid Mariano; Santamaria David;

  • 作者单位

    CNIO, Expt Oncol Mol Oncol Programme, Madrid 28029, Spain;

    CNIO, Expt Oncol Mol Oncol Programme, Madrid 28029, Spain|Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA;

    CNIO, Expt Oncol Mol Oncol Programme, Madrid 28029, Spain;

    CNIO, Bioinformat Unit, Struct Biol & Biocomp Programme, Madrid 28029, Spain;

    CNIO, Expt Oncol Mol Oncol Programme, Madrid 28029, Spain;

    Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA;

    Canc Res UK Manchester Inst, Mol Oncol Grp, Manchester M20 4BX, Lancs, England;

    Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA;

    Harvard Med Sch, Boston Childrens Hosp, Dept Pathol, Boston, MA USA;

    Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA;

    CNIO, Expt Oncol Mol Oncol Programme, Madrid 28029, Spain;

    CNIO, Expt Oncol Mol Oncol Programme, Madrid 28029, Spain|Univ Bordeaux, INSERM, U1218, ACT Lab,IECB, F-33600 Pessac, France;

  • 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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