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首页> 外文期刊>Nature >COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
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COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

机译：COT通过MAP激酶途径重新激活来驱动对RAF抑制的抵抗

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摘要

Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ～600 kinase and kinase-related open reading frames (ORFs) in parallel to inter-rogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway ago-nist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into res-istance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.%对携带B-RAF基因突变的黑素瘤患者所进行的临床试验,用B-RAF澈酶抑制因子PLX4032产生了很有希望的结果,但很多患者接着又产生了抵抗力.现在,两篇论文揭示了这种抵抗力的可能机制.Nazarian等人报告说,黑素瘤能够产生抵抗力是由于N-RAS的突变或PDGFR卢表达的增加,而Johannessen等人报告说,这种抵抗力是由于MAP3K8/COT的增多.这些机制中的每一个似乎都适用于在最近用PLX4032进行的临床试验中的患者,但同时令人吃惊的是,没有发现二次B-RAF突变.
机译：在50-70％的恶性黑色素瘤中发现了丝氨酸/苏氨酸激酶B-RAF（也称为BRAF）中的致癌突变。临床前研究表明，B-RAF（V600E）突变预示着黑色素瘤中对促分裂原活化蛋白激酶（MAPK）信号级联的依赖性-一项观察结果已通过RAF和MEK抑制剂在临床试验中的成功验证。然而，针对靶向抗癌治疗剂的临床反应经常被从头或获得性耐药所混淆。以阐明替代性“可滥用”靶点的方式鉴定耐药机制，可能会为有效的长期治疗策略提供依据。在这里，我们表达了〜600种激酶和与激酶相关的开放阅读框（ORF），与对选择性RAF激酶抑制剂的抗药性平行。我们将MAP3K8（编码COT / Tpl2的基因）确定为MAPK通路的前向驱动者，它对B-RAF（V600E）细胞系中的RAF抑制产生抗性。 COT主要通过不需要RAF信号的依赖MEK的机制来激活ERK。此外，COT的表达与B-RAF（V600E）培养的细胞系从头产生的耐药性以及在用MEK或RAF抑制剂治疗后复发的患者获得的黑素瘤细胞和组织中获得的耐药性有关。我们进一步确定组合MAPK途径抑制或靶向COT激酶活性作为在这种情况下减少MAPK途径活化的可能治疗策略。在一起，这些结果为涉及MAPK途径的耐药机制提供了新见解，并阐明了一种整合方法，通过该方法高通量功能筛选可以为新型治疗策略的发展提供信息。％对携带B-RAF基因突变的黑素瘤患者所进行的临床试验，用B-RAF澈酶抑制因子PLX4032产生了很有希望的结果，但很多患者随后又产生了抵抗力。现在，两篇论文揭示了这种抵抗力的可能机制.Nazarian等人报告说，黑素瘤能够产生抵抗力是由于N-RAS的突变或PDGFR卢表达的增加，而约翰内森等人报告说，这种抵抗力是由于MAP3K8 / COT的增加。这些机制中的每一个似乎都适用于在最近使用PLX4032进行的临床试验中的患者，但同时令人吃吃惊的是，没有发现二次B-RAF突变。

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  • 来源
    《Nature》 |2010年第7326期|p.968-972ⅴ|共6页
  • 作者

    Cory M. Johannessen; Jesse S. Boehm; So Young Kim; Sapana R. Thomas; Leslie Wardwell; Laura A. Johnson; Caroline M. Emery; Nicolas Stransky; Alexandria P. Cogdill; Jordi Barretina; Giordano Caponigro; Haley Hieronymus; Ryan R. Murray; Kourosh Salehi-Ashtiani; David E. Hill; Marc Vidal; Jean J. Zhao; Xiaoping Yang; Ozan Alkan; Sungjoon Kim; Jennifer L. Harris; Christopher J. Wilson; Vic E. Myer; Peter M. Finan; David E. Root; Thomas M. Roberts; Todd Golub; Keith T. Flaherty; Reinhard Dummer; Barbara L. Weber; William R. Sellers; Robert Schlegel; Jennifer A. Wargo; William C. Hahn; Levi A. Garraway;

  • 作者单位

    Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA,Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Division of Surgical Oncology, Medical Oncology and Dermatology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA;

    rnDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA;

    rnDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnDivision of Surgical Oncology, Medical Oncology and Dermatology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA,Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA;

    rnNovartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA,Department of Pediatnc Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA;

    rnCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnCenter for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnNovartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA;

    rnNovartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA;

    rnNovartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA,Department of Pediatnc Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA;

    rnDivision of Surgical Oncology, Medical Oncology and Dermatology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA;

    rnNovartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA;

    rnNovartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA;

    rnNovartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA;

    rnDivision of Surgical Oncology, Medical Oncology and Dermatology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA,Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA;

    rnBroad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA,Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA;

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