{"title":"Emerging drug profile: JAK inhibitors.","authors":"Alexander Coltoff, Andrew Kuykendall","doi":"10.1080/10428194.2024.2353434","DOIUrl":null,"url":null,"abstract":"<p><p>Dysregulated JAK/STAT hyperactivity is essential to the pathogenesis of myelofibrosis, and JAK inhibitors are the first-line treatment option for many patients. There are four FDA-approved JAK inhibitors for patients with myelofibrosis. Single-agent JAK inhibition can improve splenomegaly, symptom burden, cytopenias, and possibly survival in patients with myelofibrosis. Despite their efficacy, JAK inhibitors produce variable or short-lived responses, in part due to the large network of cooperating signaling pathways and downstream targets of JAK/STAT, which mediates upfront or acquired resistance to JAK inhibitors. Synergistic inhibition of JAK/STAT accessory pathways can increase the rates and duration of response for patients with myelofibrosis. Two recently reported, placebo-controlled phase III trials of novel agents added to JAK inhibition met their primary endpoint, and additional late-stage studies are ongoing. This paper will review role of dysregulated JAK/STAT signaling, biological plausible additional therapeutic targets and the recent advancements in combination strategies with JAK inhibitors for myelofibrosis.</p>","PeriodicalId":18047,"journal":{"name":"Leukemia & Lymphoma","volume":null,"pages":null},"PeriodicalIF":2.2000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia & Lymphoma","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/10428194.2024.2353434","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/5/13 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Dysregulated JAK/STAT hyperactivity is essential to the pathogenesis of myelofibrosis, and JAK inhibitors are the first-line treatment option for many patients. There are four FDA-approved JAK inhibitors for patients with myelofibrosis. Single-agent JAK inhibition can improve splenomegaly, symptom burden, cytopenias, and possibly survival in patients with myelofibrosis. Despite their efficacy, JAK inhibitors produce variable or short-lived responses, in part due to the large network of cooperating signaling pathways and downstream targets of JAK/STAT, which mediates upfront or acquired resistance to JAK inhibitors. Synergistic inhibition of JAK/STAT accessory pathways can increase the rates and duration of response for patients with myelofibrosis. Two recently reported, placebo-controlled phase III trials of novel agents added to JAK inhibition met their primary endpoint, and additional late-stage studies are ongoing. This paper will review role of dysregulated JAK/STAT signaling, biological plausible additional therapeutic targets and the recent advancements in combination strategies with JAK inhibitors for myelofibrosis.
JAK/STAT活性失调是骨髓纤维化发病机制的关键,JAK抑制剂是许多患者的一线治疗选择。目前有四种 JAK 抑制剂获 FDA 批准用于骨髓纤维化患者。单药 JAK 抑制剂可改善骨髓纤维化患者的脾脏肿大、症状负担、细胞减少症,并可能改善患者的存活率。尽管疗效显著,但JAK抑制剂产生的反应不一或持续时间较短,部分原因是JAK/STAT的信号通路和下游靶点之间存在庞大的合作网络,从而导致患者对JAK抑制剂产生前期或获得性耐药性。协同抑制 JAK/STAT 辅助通路可提高骨髓纤维化患者的应答率并延长应答时间。最近报道的两项在JAK抑制剂基础上添加新型药物的安慰剂对照III期试验达到了主要终点,其他后期研究正在进行中。本文将综述JAK/STAT信号传导失调的作用、生物学上可信的其他治疗靶点,以及近期骨髓纤维化与JAK抑制剂联合治疗策略的进展。
期刊介绍:
Leukemia & Lymphoma in its fourth decade continues to provide an international forum for publication of high quality clinical, translational, and basic science research, and original observations relating to all aspects of hematological malignancies. The scope ranges from clinical and clinico-pathological investigations to fundamental research in disease biology, mechanisms of action of novel agents, development of combination chemotherapy, pharmacology and pharmacogenomics as well as ethics and epidemiology. Submissions of unique clinical observations or confirmatory studies are considered and published as Letters to the Editor