JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment
JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment
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JAK2 的 JAK1 依赖性转磷酸化限制了选择性 JAK2 抑制剂对长期治疗的抗纤维化作用
DOI：
10.1136/annrheumdis-2016-210911
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发表时间：
2017
影响因子：
27.4
通讯作者：
Distler JH
中科院分区：
文献类型：
--
作者：
Zhang Y;Liang R;Chen C-W;Mallano T;Dees C;Distler A;Reich A;Bergmann C;Ramming A;Gelse K;Milenz D;Distler OSchett G;Distler JH
目的Janus kinase2(JAK2)最近被认为是转化生长因子-β促纤维化作用的一种新的下游介体。尽管JAK2抑制剂在临床上用于治疗骨髓增生异常综合征，但患者往往很快就会产生耐药性。肿瘤细胞可以通过JAK1对JAK2的突变非突变反式激活来逃避选择性JAK2抑制剂的治疗效果。在这里，我们使用选择性JAK2抑制作为一个模型来检验这一假说，即慢性治疗可能通过促进成纤维细胞中的非生理性信号通路而引发抵抗。方法在培养的成纤维细胞和实验性的真皮和肺纤维化中，分析长期使用选择性JAK2抑制剂和通过JAK1依赖的转磷酸化重新激活JAK2信号的抗纤维化效果。JAK1/JAK2联合抑制和与HSP90抑制剂共处理是克服耐药性的策略。结果选择性JAK2抑制剂对成纤维细胞的抗纤维化作用随时间延长而减弱，JAK2信号被JAK1依赖的JAK2转磷酸化重新激活。这种重新激活可以通过抑制HSP90来阻止，这会破坏JAK2蛋白的稳定性，或者联合使用JAK1/JAK2抑制剂。在博莱霉素性肺纤维化和真皮纤维化中，JAK1/JAK2抑制剂联合或JAK2抑制剂与HSP90抑制剂联合治疗比单独使用JAK2抑制剂更有效。结论成纤维细胞可通过诱导JAK2非生理性依赖的JAK2反式激活而产生对JAK2抑制剂慢性治疗的抵抗力，通过共同抑制JAK1或HSP90来抑制这一代偿信号通路，从而在长期治疗的同时维持JAK2抑制的抗纤维化作用。
ObjectivesJanus kinase 2 (JAK2) has recently been described as a novel downstream mediator of the pro-fibrotic effects of transforming growth factor-β. Although JAK2 inhibitors are in clinical use for myelodysplastic syndromes, patients often rapidly develop resistance. Tumour cells can escape the therapeutic effects of selective JAK2 inhibitors by mutation-independent transactivation of JAK2 by JAK1. Here, we used selective JAK2 inhibition as a model to test the hypothesis that chronic treatment may provoke resistance by facilitating non-physiological signalling pathways in fibroblasts.MethodsThe antifibrotic effects of long-term treatment with selective JAK2 inhibitors and reactivation of JAK2 signalling by JAK1-dependent transphosphorylation was analysed in cultured fibroblasts and experimental dermal and pulmonary fibrosis. Combined JAK1/JAK2 inhibition and co-treatment with an HSP90 inhibitor were evaluated as strategies to overcome resistance.ResultsThe antifibrotic effects of selective JAK2 inhibitors on fibroblasts decreased with prolonged treatment as JAK2 signalling was reactivated by JAK1-dependent transphosphorylation of JAK2. This reactivation could be prevented by HSP90 inhibition, which destabilised JAK2 protein, or with combined JAK1/JAK2 inhibitors. Treatment with combined JAK1/JAK2 inhibitors or with JAK2 inhibitors in combination with HSP90 inhibitors was more effective than monotherapy with JAK2 inhibitors in bleomycin-induced pulmonary fibrosis and in adTBR-induced dermal fibrosis.ConclusionFibroblasts can develop resistance to chronic treatment with JAK2 inhibitors by induction of non-physiological JAK1-dependent transactivation of JAK2 and that inhibition of this compensatory signalling pathway, for example, by co-inhibition of JAK1 or HSP90 is important to maintain the antifibrotic effects of JAK2 inhibition with long-term treatment.
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影响因子：
15.9
作者：
Marubayashi, Sachie;Koppikar, Priya;Levine, Ross L.
通讯作者：
Levine, Ross L.
影响因子：
27.4
作者：
Khodzhigorova, Aisa;Distler, Alfiya;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.
影响因子：
20.3
作者：
Heine, Annkristin;Held, Stefanie Andrea Erika;Brossart, Peter
通讯作者：
Brossart, Peter
影响因子：
27.4
作者：
Zhang, Yun;Dees, Clara;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.
影响因子：
27.4
作者：
M. Tomčík;P. Zerr;J. Pitkowski;K. Palumbo-Zerr;J. Avouac;O. Distler;R. Bečvář;L. Šenolt;G. Schett;J. Distler
通讯作者：
M. Tomčík;P. Zerr;J. Pitkowski;K. Palumbo-Zerr;J. Avouac;O. Distler;R. Bečvář;L. Šenolt;G. Schett;J. Distler