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Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS

机译：具有3类BRAF突变体的肿瘤对激活RAS的抑制敏感

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摘要

Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2)(1). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.
机译：在人类肿瘤中已鉴定出约200个BRAF突变等位基因。激活的BRAF突变体会引起与GTP结合的RAS的反馈抑制，是RAS独立的，并以活性单体（1类）或组成型活性二聚体（2类）（1）发出信号。在这里，我们描述了第三类BRAF突变体，即那些激酶活性受损或激酶死亡的突变体。这些突变体对ERK介导的反馈敏感，其信号激活是RAS依赖性的。该突变体比野生型BRAF与RAS-GTP的结合更紧密，并且它们与野生型CRAF的结合和激活得到增强，从而导致ERK信号转导增加。该模型表明，尽管有ERK依赖性反馈，这些突变体在肿瘤中的信号失调仍需要维持RAS激活的共存机制。与此假设一致，具有这些3类BRAF突变的黑色素瘤也包含RAS突变或NF1缺失。相比之下，在具有3类BRAF突变体的肺癌和大肠癌中，RAS通常被受体酪氨酸激酶信号激活。这些肿瘤对受体酪氨酸激酶抑制剂对RAS活化的抑制敏感。因此，我们在人类肿瘤中定义了BRAF突变体的三个不同功能类别。突变体通过不同的机制激活ERK信号传导，从而决定了它们对该途径的治疗性抑制剂的敏感性。

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  • 来源
    《Nature》 |2017年第7666期|234-238|共5页
  • 作者

    Yao Zhan; Yaeger Rona; Rodrik-Outmezguine Vanessa S.; Tao Anthony; Torres Neilawattie M.; Chang Matthew T.; Drosten Matthias; Zhao Huiyong; Cecchi Fabiola; Hembrough Todd; Michels Judith; Baumert Herve; Miles Linde; Campbell Naomi M.; de Stanchina Elisa; Solit David B.; Barbacid Mariano; Taylor Barry S.; Rosen Neal;

  • 作者单位

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

    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA;

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

    New York Univ, Coll Arts & Sci, Ctr Neural Sci, New York, NY 10012 USA;

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

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA|Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 USA;

    CNIO, Mol Oncol Programme, Melchor Fernandez Almagro 3, Madrid 28029, Spain;

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

    NantOmics LLC, Mol Oncol Grp, 9600 Med Ctr Dr,Suite 300, Rockville, MD 20854 USA;

    NantOmics LLC, Mol Oncol Grp, 9600 Med Ctr Dr,Suite 300, Rockville, MD 20854 USA;

    Dept Med Oncol, Gustave Roussy Canc Campus, Villejuif, France|Univ Paris Sud, Fac Med, Le Kremlin Bicetre, France;

    St Joseph Hosp, Urol Dept, Paris, France;

    Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA|Johns Hopkins Univ, Dept Pharmacol & Mol Sci, Anti Canc Drug Dev Grad Training Program, Baltimore, MD 21205 USA;

    Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10065 USA;

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

    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, New York, NY 10065 USA;

    CNIO, Mol Oncol Programme, Melchor Fernandez Almagro 3, Madrid 28029, Spain;

    Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, New York, NY 10065 USA;

    Mem Sloan Kettering Canc Ctr, Program Mol Pharmacol, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA|Mem Sloan Kettering Canc Ctr, Ctr Mech Based Therapeut, New York, NY 10065 USA;

  • 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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