Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, Germany.
Department of Dermatology, Venereology and Allergology, Wrocław Medical University, Wrocław, Poland.
Ann Rheum Dis. 2017 Aug;76(8):1467-1475. doi: 10.1136/annrheumdis-2016-210911. Epub 2017 May 6.
Janus 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.
The 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.
The 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.
Fibroblasts 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.
Janus 激酶 2（JAK2）最近被描述为转化生长因子-β促纤维化作用的新下游介质。尽管 JAK2 抑制剂已用于骨髓增生异常综合征的临床治疗，但患者常迅速产生耐药性。肿瘤细胞可通过 JAK1 非突变依赖性转磷酸化激活 JAK2，逃避选择性 JAK2 抑制剂的治疗作用。在这里，我们使用选择性 JAK2 抑制作为模型，测试长期治疗是否会通过促进成纤维细胞中非生理信号通路而引发耐药的假设。
在培养的成纤维细胞以及实验性皮肤和肺纤维化中，分析了长期使用选择性 JAK2 抑制剂的抗纤维化作用以及 JAK1 依赖性转磷酸化对 JAK2 信号的再激活作用。评估了联合 JAK1/JAK2 抑制和 HSP90 抑制剂共同治疗作为克服耐药的策略。
随着 JAK2 信号被 JAK1 依赖性 JAK2 转磷酸化重新激活，选择性 JAK2 抑制剂对成纤维细胞的抗纤维化作用随着治疗时间的延长而降低。HSP90 抑制可防止这种再激活，HSP90 抑制可使 JAK2 蛋白不稳定，或与联合 JAK1/JAK2 抑制剂联合使用。与 JAK2 抑制剂单药治疗相比，联合 JAK1/JAK2 抑制剂或 JAK2 抑制剂联合 HSP90 抑制剂治疗在博来霉素诱导的肺纤维化和 adTBR 诱导的皮肤纤维化中更有效。
成纤维细胞可通过诱导非生理性 JAK1 依赖性 JAK2 转激活对 JAK2 抑制剂的慢性治疗产生耐药性，抑制这种代偿性信号通路（例如，通过 JAK1 或 HSP90 的联合抑制）对于维持 JAK2 抑制的抗纤维化作用非常重要长期治疗。
