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Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy

机译：异二聚体JAK-STAT激活是JAK2抑制剂治疗的持久机制

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摘要

The identification of somatic activating mutations in JAK2 (refs 1-4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK-STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors.
机译：在大多数患有骨髓增生性肿瘤（MPN）的患者中，JAK2（参考文献1-4）和血小板生成素受体基因（MPL）中的体细胞激活突变的鉴定导致了JAK2激酶抑制剂的临床开发。 JAK2抑制剂疗法可改善MPN相关的脾肿大和全身症状，但在大多数MPN患者中并未显着减少或消除MPN克隆。因此，我们试图表征尽管长期抑制JAK2，MPN细胞仍然存在的机制。在这里，我们显示JAK2抑制剂的持久性与JAK-STAT信号的重新激活以及活化的JAK2和JAK1或TYK2之间的异二聚化有关，这与其他JAK激酶反式激活JAK2一致。此外，该现象是可逆的：JAK2抑制剂的撤出与对JAK2激酶抑制剂的重新敏化以及JAK2表达的可逆变化有关。我们在细胞系，鼠类模型和接受JAK2抑制剂治疗的患者中看到了JAK2异二聚体的增加和JAK2的持续活化。 RNA干扰和药理研究表明，JAK2抑制剂持久性细胞仍然依赖于JAK2蛋白的表达。因此，导致JAK2降解的疗法可在持久性细胞中保持效力，并可为使用JAK2抑制剂治疗的JAK2依赖性恶性肿瘤患者提供更多益处。

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  • 来源
    《Nature》 |2012年第7414期|p.155-159|共5页
  • 作者

    Priya Koppikar; Neha Bhagwat; Outi Kilpivaara; Taghi Manshouri; Mazhar Adli; Todd Hricik; Fan Liu; Lindsay M. Saunders; Ann Mullally; Omar Abdel-Wahab; Laura Leung; Abby Weinstein; Sachie Marubayashi; Aviva God; Mithat Goenen; Zeev Estrov; Benjamin L. Ebert; Gabriela Chiosis; Stephen D. Nimer; Bradley E. Bernstein; Srdan Verstovsek; Ross L. Levine;

  • 作者单位

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA';

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA',Gerstner Sloan- Kettering Graduate School in Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA';

    M. D. Anderson Cancer Center, Houston, Texas 77030, USA;

    Howard Hughes Medical Institute, Department of Pathology, Massachusetts General Hospital and Broad Institute of Harvard, Massachusetts Institute of Technology, Massachusetts 02114, USA;

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA';

    Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA',Gerstner Sloan- Kettering Graduate School in Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA',Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA';

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA';

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA';

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA';

    Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    M. D. Anderson Cancer Center, Houston, Texas 77030, USA;

    Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA,Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA;

    Howard Hughes Medical Institute, Department of Pathology, Massachusetts General Hospital and Broad Institute of Harvard, Massachusetts Institute of Technology, Massachusetts 02114, USA;

    M. D. Anderson Cancer Center, Houston, Texas 77030, USA;

    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA',Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, New York 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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