法尼基转移酶(FTase)抑制剂增加伊马替尼对KIT突变体的抑制作用。

IF 1.6 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zhaoyang Fan, Liangying Zhang, Shaoting Zhang, Anbu Liu, Shujing Li, Xu Cao, Jinhai Tian, Sien Zhao, Jianmin Sun
{"title":"法尼基转移酶(FTase)抑制剂增加伊马替尼对KIT突变体的抑制作用。","authors":"Zhaoyang Fan,&nbsp;Liangying Zhang,&nbsp;Shaoting Zhang,&nbsp;Anbu Liu,&nbsp;Shujing Li,&nbsp;Xu Cao,&nbsp;Jinhai Tian,&nbsp;Sien Zhao,&nbsp;Jianmin Sun","doi":"10.52547/rbmb.12.1.74","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Mutations in the receptor tyrosine kinase KIT are the major cause of gastrointestinal stromal tumors. KIT-mediated activation of the RAS/RAF/MEK/ERK and PI3 kinase/AKT pathways plays an important role in KIT mutant-mediated cell transformation.</p><p><strong>Methods: </strong>The frequently seen primary KIT mutations W557K558del and V560D, and the secondary KIT mutations V654A and N822K, in gastrointestinal stromal tumors were stably transfected into Ba/F3 cells. Cell proliferation was examined with a CCK kit, and cell survival and cell cycle were examined by flow cytometry. Cell signaling was examined by western blot.</p><p><strong>Results: </strong>We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Correspondingly, both wild-type and KIT mutant-mediated cell survival and proliferation were inhibited by both inhibitors. Imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. In our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and KIT mutants. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors.</p><p><strong>Conclusions: </strong>Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.</p>","PeriodicalId":45319,"journal":{"name":"Reports of Biochemistry and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":1.6000,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10505455/pdf/rbmb-12-74.pdf","citationCount":"0","resultStr":"{\"title\":\"Farnesyltransferase (FTase) Inhibitors Increase Inhibition of KIT Mutants by Imatinib.\",\"authors\":\"Zhaoyang Fan,&nbsp;Liangying Zhang,&nbsp;Shaoting Zhang,&nbsp;Anbu Liu,&nbsp;Shujing Li,&nbsp;Xu Cao,&nbsp;Jinhai Tian,&nbsp;Sien Zhao,&nbsp;Jianmin Sun\",\"doi\":\"10.52547/rbmb.12.1.74\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Mutations in the receptor tyrosine kinase KIT are the major cause of gastrointestinal stromal tumors. KIT-mediated activation of the RAS/RAF/MEK/ERK and PI3 kinase/AKT pathways plays an important role in KIT mutant-mediated cell transformation.</p><p><strong>Methods: </strong>The frequently seen primary KIT mutations W557K558del and V560D, and the secondary KIT mutations V654A and N822K, in gastrointestinal stromal tumors were stably transfected into Ba/F3 cells. Cell proliferation was examined with a CCK kit, and cell survival and cell cycle were examined by flow cytometry. Cell signaling was examined by western blot.</p><p><strong>Results: </strong>We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Correspondingly, both wild-type and KIT mutant-mediated cell survival and proliferation were inhibited by both inhibitors. Imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. In our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and KIT mutants. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors.</p><p><strong>Conclusions: </strong>Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.</p>\",\"PeriodicalId\":45319,\"journal\":{\"name\":\"Reports of Biochemistry and Molecular Biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.6000,\"publicationDate\":\"2023-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10505455/pdf/rbmb-12-74.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Reports of Biochemistry and Molecular Biology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.52547/rbmb.12.1.74\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Reports of Biochemistry and Molecular Biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.52547/rbmb.12.1.74","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

背景:受体酪氨酸激酶KIT的突变是胃肠道间质瘤的主要原因。KIT介导的RAS/RAF/MEK/ERK和PI3激酶/AKT途径的激活在KIT突变体介导的细胞转化中起着重要作用。方法:将胃肠道间质瘤中常见的原代KIT突变W557K558del和V560D,以及继发性KIT突变V654A和N822K稳定转染到Ba/F3细胞中。用CCK试剂盒检测细胞增殖,用流式细胞术检测细胞存活率和细胞周期。通过蛋白质印迹检测细胞信号传导。结果:我们发现法尼基转移酶抑制剂替皮法尼和洛那法尼抑制RAS活性,抑制野生型和KIT突变体介导的ERK激活,这通常发生在胃肠道间质瘤中。相应地,野生型和KIT突变体介导的细胞存活和增殖都受到两种抑制剂的抑制。伊马替尼在临床上被用作胃肠道间质瘤的一线靶向治疗。在我们的研究中,两种抑制剂都增加了伊马替尼介导的对野生型和KIT突变体诱导的细胞存活和增殖的抑制。与原发性KIT突变类似,KIT诱导的ERK激活和细胞反应的继发性突变被两种抑制剂抑制。结论:我们的研究结果表明,法尼基转移酶抑制剂单独或与伊马替尼联合治疗携带KIT突变的胃肠道间质瘤具有潜在的益处。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Farnesyltransferase (FTase) Inhibitors Increase Inhibition of KIT Mutants by Imatinib.

Background: Mutations in the receptor tyrosine kinase KIT are the major cause of gastrointestinal stromal tumors. KIT-mediated activation of the RAS/RAF/MEK/ERK and PI3 kinase/AKT pathways plays an important role in KIT mutant-mediated cell transformation.

Methods: The frequently seen primary KIT mutations W557K558del and V560D, and the secondary KIT mutations V654A and N822K, in gastrointestinal stromal tumors were stably transfected into Ba/F3 cells. Cell proliferation was examined with a CCK kit, and cell survival and cell cycle were examined by flow cytometry. Cell signaling was examined by western blot.

Results: We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Correspondingly, both wild-type and KIT mutant-mediated cell survival and proliferation were inhibited by both inhibitors. Imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. In our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and KIT mutants. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors.

Conclusions: Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Reports of Biochemistry and Molecular Biology
Reports of Biochemistry and Molecular Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
2.80
自引率
23.50%
发文量
60
审稿时长
10 weeks
期刊介绍: The Reports of Biochemistry & Molecular Biology (RBMB) is the official journal of the Varastegan Institute for Medical Sciences and is dedicated to furthering international exchange of medical and biomedical science experience and opinion and a platform for worldwide dissemination. The RBMB is a medical journal that gives special emphasis to biochemical research and molecular biology studies. The Journal invites original and review articles, short communications, reports on experiments and clinical cases, and case reports containing new insights into any aspect of biochemistry and molecular biology that are not published or being considered for publication elsewhere. Publications are accepted in the form of reports of original research, brief communications, case reports, structured reviews, editorials, commentaries, views and perspectives, letters to authors, book reviews, resources, news, and event agenda.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信