Meyer Sara C
Division of Hematology, Department of Biomedicine, University Hospital Basel, Hebelstrasse 20, Basel 4031, Switzerland.
Hematol Oncol Clin North Am. 2017 Aug;31(4):627-642. doi: 10.1016/j.hoc.2017.04.003. Epub 2017 May 13.
Myeloproliferative neoplasms are driven by activated JAK2 signaling due to somatic mutations in JAK2, the thrombopoietin receptor MPL or the chaperone calreticulin in hematopoietic stem/progenitor cells. JAK2 inhibitors have been developed, but despite clinical benefits, they do not signficantly reduce the mutant clone. Loss of response to JAK2 inhibitors occurs and several mechanisms of resistance, genetic and functional, have been identified. Resistance mutations have not been reported in MPN patients suggesting incomplete target inhibition. Alternative targeting of JAK2 by HSP90 inhibitors or type II JAK2 inhibition overcomes resistance to current JAK2 inhibitors. Additional combined therapy approaches are currently being evaluated.
骨髓增殖性肿瘤由造血干/祖细胞中JAK2、血小板生成素受体MPL或伴侣蛋白钙网蛋白的体细胞突变导致的JAK2信号激活所驱动。JAK2抑制剂已被研发出来，但尽管有临床益处，它们并不能显著减少突变克隆。对JAK2抑制剂的反应丧失会发生，并且已经确定了几种遗传和功能上的耐药机制。MPN患者中尚未报告耐药突变，提示靶点抑制不完全。通过HSP90抑制剂对JAK2进行替代靶向或II型JAK2抑制可克服对当前JAK2抑制剂的耐药性。目前正在评估其他联合治疗方法。
