Alina Makeeva, Simona Stivala, Elena Ratti, Laetitia Clauss, Etnik Sheremeti, Michel Arock, Martina Konantz, Karin Hartmann
{"title":"Fedratinib and gandotinib induce apoptosis and enhance the efficacy of tyrosine kinase inhibitors in human mast cells.","authors":"Alina Makeeva, Simona Stivala, Elena Ratti, Laetitia Clauss, Etnik Sheremeti, Michel Arock, Martina Konantz, Karin Hartmann","doi":"10.62347/TYTU4465","DOIUrl":null,"url":null,"abstract":"<p><p>Mastocytosis is characterized by an abnormal accumulation of mast cells (MC) in various organs. In most patients, the disease is driven by the <i>KIT</i> D816V mutation, leading to activation of the KIT receptor and subsequent downstream signaling, including the JAK/STAT pathway. In recent years, KIT-targeting tyrosine kinase inhibitors (TKI) have emerged for the treatment of systemic mastocytosis; however, the overall response rate is often not sufficient. In this study, we investigated whether targeting the JAK/STAT pathway might be a novel treatment approach in mastocytosis. Using human MC lines carrying the <i>KIT</i> D816V mutation and human primary cord blood-derived MC, we examined the effects of different JAK inhibitors. Our findings revealed that the JAK inhibitors fedratinib and gandotinib decreased viability, reduced proliferation, and induced apoptosis in <i>KIT</i> D816V-positive MC lines (HMC-1.2 and ROSA <sup><i>KIT</i> D816V</sup>). In contrast, ruxolitinib, baricitinib, upadacitinib and abrocitinib failed to affect MC functions. Combinatorial treatment with fedratinib, gandotinib and the two TKI avapritinib and midostaurin was more effective than treatment with TKI alone. Fedratinib also induced apoptosis and enhanced the efficacy of TKI in primary cord blood-derived MC. These results indicate that fedratinib and gandotinib, but not the other JAK inhibitors used in this study, can suppress viability and induce apoptosis in <i>KIT</i> D816V-mutant and <i>KIT</i> WT MC and increase effects of TKI. These findings suggest to explore fedratinib and gandotinib as novel treatment option in mastocytosis.</p>","PeriodicalId":7437,"journal":{"name":"American journal of cancer research","volume":"15 1","pages":"84-98"},"PeriodicalIF":3.6000,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11815366/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of cancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.62347/TYTU4465","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Mastocytosis is characterized by an abnormal accumulation of mast cells (MC) in various organs. In most patients, the disease is driven by the KIT D816V mutation, leading to activation of the KIT receptor and subsequent downstream signaling, including the JAK/STAT pathway. In recent years, KIT-targeting tyrosine kinase inhibitors (TKI) have emerged for the treatment of systemic mastocytosis; however, the overall response rate is often not sufficient. In this study, we investigated whether targeting the JAK/STAT pathway might be a novel treatment approach in mastocytosis. Using human MC lines carrying the KIT D816V mutation and human primary cord blood-derived MC, we examined the effects of different JAK inhibitors. Our findings revealed that the JAK inhibitors fedratinib and gandotinib decreased viability, reduced proliferation, and induced apoptosis in KIT D816V-positive MC lines (HMC-1.2 and ROSA KIT D816V). In contrast, ruxolitinib, baricitinib, upadacitinib and abrocitinib failed to affect MC functions. Combinatorial treatment with fedratinib, gandotinib and the two TKI avapritinib and midostaurin was more effective than treatment with TKI alone. Fedratinib also induced apoptosis and enhanced the efficacy of TKI in primary cord blood-derived MC. These results indicate that fedratinib and gandotinib, but not the other JAK inhibitors used in this study, can suppress viability and induce apoptosis in KIT D816V-mutant and KIT WT MC and increase effects of TKI. These findings suggest to explore fedratinib and gandotinib as novel treatment option in mastocytosis.
期刊介绍:
The American Journal of Cancer Research (AJCR) (ISSN 2156-6976), is an independent open access, online only journal to facilitate rapid dissemination of novel discoveries in basic science and treatment of cancer. It was founded by a group of scientists for cancer research and clinical academic oncologists from around the world, who are devoted to the promotion and advancement of our understanding of the cancer and its treatment. The scope of AJCR is intended to encompass that of multi-disciplinary researchers from any scientific discipline where the primary focus of the research is to increase and integrate knowledge about etiology and molecular mechanisms of carcinogenesis with the ultimate aim of advancing the cure and prevention of this increasingly devastating disease. To achieve these aims AJCR will publish review articles, original articles and new techniques in cancer research and therapy. It will also publish hypothesis, case reports and letter to the editor. Unlike most other open access online journals, AJCR will keep most of the traditional features of paper print that we are all familiar with, such as continuous volume, issue numbers, as well as continuous page numbers to retain our comfortable familiarity towards an academic journal.