Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms
Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms
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DOI：
10.1182/blood-2014-01-547760
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发表时间：
2014-03-27
期刊：
影响因子：
20.3
通讯作者：
Levine, Ross L.
中科院分区：
文献类型：
--
作者：
Bhagwat, Neha;Koppikar, Priya;Levine, Ross L.
在骨髓增生性肿瘤(MPN)患者中发现JAK2/MPL突变，导致临床上开发出治疗MPN的Janus Kinase(JAK)抑制剂。这些抑制剂改善了体质症状和脾肿大，但不能显著降低患者的突变等位基因负担。我们最近发现，长期暴露于JAK抑制剂通过JAK2的反式激活和JAK信号转导和转录激活子信号的持续存在导致了抑制剂的持续存在。我们进行了遗传学和药理学研究，以确定改进的JAK2抑制是否会在MPN模型和原始样本中显示出更高的疗效。JAK2在体内的缺失导致JAK抑制剂所未见的疾病负担的显著降低，而慢性Ruxolitinib治疗后JAK2的缺失显著降低了突变的等位基因负担。这表明在慢性JAK抑制的背景下存活的MPN细胞中JAK2仍然是一个重要的靶点。热休克蛋白90(HSP90)抑制剂PU-H71和Ruxolitinib联合治疗可减少总JAK2和磷酸化JAK2，对下游信号转导的抑制作用强于Ruxolitinib单独治疗。与单用鲁索利替尼相比，联合治疗改善了血细胞计数、脾重量，并减少了骨髓纤维化。这些数据表明，增加JAK2靶向性的替代方法，包括联合JAK/HSP90抑制剂治疗，在临床环境中是必要的。
The discovery of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) led to clinical development of Janus kinase (JAK) inhibitors for treatment of MPN. These inhibitors improve constitutional symptoms and splenomegaly but do not significantly reduce mutant allele burden in patients. We recently showed that chronic exposure to JAK inhibitors results in inhibitor persistence via JAK2 transactivation and persistent JAK-signal transducer and activator of transcription signaling. We performed genetic and pharmacologic studies to determine whether improved JAK2 inhibition would show increased efficacy in MPN models and primary samples. Jak2 deletion in vivo led to profound reduction in disease burden not seen with JAK inhibitors, and deletion of Jak2 following chronic ruxolitinib therapy markedly reduced mutant allele burden. This demonstrates that JAK2 remains an essential target in MPN cells that survive in the setting of chronic JAK inhibition. Combination therapy with the heat shock protein 90 (HSP90) inhibitor PU-H71 and ruxolitinib reduced total and phospho-JAK2 and achieved more potent inhibition of downstream signaling than ruxolitinib monotherapy. Combination treatment improved blood counts, spleen weights, and reduced bone marrow fibrosis compared with ruxolitinib alone. These data suggest alternate approaches that increase JAK2 targeting, including combination JAK/HSP90 inhibitor therapy, are warranted in the clinical setting.