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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >MEK1 mutations confer resistance to MEK and B-RAF inhibition
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MEK1 mutations confer resistance to MEK and B-RAF inhibition

机译：MEK1突变赋予对MEK和B-RAF抑制的抗性

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摘要

Genetic alterations that activate the mitogen-activated protein kinase (MAP kinase) pathway occur commonly in cancer. For example, the majority of melanomas harbor mutations in the BRAF oncogene, which are predicted to confer enhanced sensitivity to pharmacologic MAP kinase inhibition (e.g., RAF or MEK inhibitors). We investigated the clinical relevance of MEK dependency in melanoma by massively parallel sequencing of resistant clones generated from a MEK1 random mutagenesis screen in vitro, as well as tumors obtained from relapsed patients following treatment with AZD6244, an allosteric MEK inhibitor. Most mutations conferring resistance to MEK inhibition in vitro populated the allosteric drug binding pocket or α-helix C and showed robust (≈100-fold) resistance to allosteric MEK inhibition. Other mutations affected MEK1 codons located within or abutting the N-terminal negative regulatory helix (helix A), which also undergo gain-of-function germline mutations in cardio-facio-cutaneous (CFC) syndrome. One such mutation, MEK1(P124L), was identified in a resistant metastatic focus that emerged in a melanoma patient treated with AZD6244. Both MEK1(P124L) and MEK1(Q56P), which disrupts helix A, conferred cross-resistance to PLX4720, a selective B-RAF inhibitor. However, exposing BRAF-mutant melanoma cells to AZD6244 and PLX4720 in combination prevented emergence of resistant clones. These results affirm the importance of MEK dependency in BRAF-mutant melanoma and suggest novel mechanisms of resistance to MEK and B-RAF inhibitors that may have important clinical implications.
机译：激活有丝分裂原激活的蛋白激酶（MAP激酶）途径的遗传改变通常发生在癌症中。例如，大多数黑色素瘤在BRAF癌基因中具有突变，据预测这些突变赋予对药理MAP激酶抑制作用（例如，RAF或MEK抑制剂）的增强的敏感性。我们通过大规模平行测序从MEK1随机诱变筛选体外产生的抗性克隆，以及从变构MEK抑制剂AZD6244治疗后的复发患者中获得的肿瘤，研究了MEK依赖于黑色素瘤的临床相关性。在体外，大多数赋予对MEK抑制作用抗性的突变会填充变构药物结合袋或α-螺旋C，并表现出对变构MEK抑制作用的强大（约100倍）抗性。其他突变影响位于或邻近N端负调控螺旋（螺旋A）的MEK1密码子，其在心-面部皮肤（CFC）综合征中也会发生功能获得性生殖系突变。在用AZD6244治疗的黑色素瘤患者中出现的耐药转移灶中发现了一个这样的突变MEK1（P124L）。破坏螺旋A的MEK1（P124L）和MEK1（Q56P）均赋予了选择性B-RAF抑制剂PLX4720交叉耐药性。但是，将BRAF突变的黑色素瘤细胞联合暴露于AZD6244和PLX4720会阻止抗性克隆的出现。这些结果证实了MEK依赖在BRAF突变型黑色素瘤中的重要性，并提出了对MEK和B-RAF抑制剂耐药的新机制，可能具有重要的临床意义。

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  • 作者

    Caroline M. Emery; Krishna G. Vijayendran; Marie C. Zipser; Allison M. Sawyer; Lili Niu; Jessica J. Kim; Charles Hatton; Rajiv Chopra; Patrick A. Oberholzer; Maria B. Karpova; Laura E. MacConaill; Jianming Zhang; Nathanael S. Gray; William R. Sellers; Reinhard Dummer; Levi A. Garraway;

  • 作者单位

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;

    Department of Dermatology, University Hospital of Zurich, Zurich, CH-8091, Switzerland;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;

    Novartis Institute of BioMedical Research, Cambridge, MA 02139;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Department of Dermatology, University Hospital of Zurich, Zurich, CH-8091, Switzerland The Broad Institute, Cambridge, MA 02142;

    Department of Dermatology, University Hospital of Zurich, Zurich, CH-8091, Switzerland;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115;

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

    Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;

    Novartis Institute of BioMedical Research, Cambridge, MA 02139;

    Department of Dermatology, University Hospital of Zurich, Zurich, CH-8091, Switzerland;

    Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115 The Broad Institute, Cambridge, MA 02142;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    BRAF; drug resistance; MAP kinase; melanoma;

    机译：布拉夫耐药性;MAP激酶;黑色素瘤;

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