Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants
文献类型：期刊论文
| 作者 | Zhao, Jie; Quan, Haitian ; Xu, Yongping; Kong, Xiangqian; Jin, Lu; Lou, Liguang
|
| 刊名 | CANCER SCIENCE
 |
| 出版日期 | 2014-01 |
| 卷号 | 105期号:1页码:117-125 |
| 关键词 | Drug resistance flumatinib gastrointestinal stromal tumors imatinib mesylate sunitinib malate |
| ISSN号 | 1349-7006 |
| DOI | 10.1111/cas.12320 |
| 文献子类 | Article |
| 英文摘要 | Activating mutations in KIT have been associated with gastrointestinal stromal tumors (GISTs). The tyrosine kinase inhibitor imatinib mesylate has revolutionized the treatment of GISTs. Unfortunately, primary or acquired resistance to imatinib does occur in GISTs and forms a major problem. Although sunitinib malate, a multi-kinase inhibitor, has shown effectiveness against imatinib-resistant GISTs, recent studies have indicated that some imatinib-resistant GISTs harboring secondary mutations in the KIT activation loop were also resistant to sunitinib. Therefore, new drugs capable of overcoming the dual drug resistance of GISTs probably have potential clinical utility. In this study, we investigated the efficacy of flumatinib, an inhibitor of BCR-ABL/PDGFR/KIT, against 32D cells transformed by various KIT mutants and evaluated its potency to overcome the drug resistance of certain mutants. Interestingly, our in vitro study revealed that flumatinib effectively overcame the drug resistance of certain KIT mutants with activation loop mutations (i.e., D820G, N822K, Y823D, and A829P). Our in vivo study consistently suggested that flumatinib had superior efficacy compared with imatinib or sunitinib against 32D cells with the secondary mutation Y823D. Molecular modeling of flumatinib docked to the KIT kinase domain suggested a special mechanism underlying the capability of flumatinib to overcome the drug-resistance conferred by activation loop mutations. These findings suggest that flumatinib could be a promising therapeutic agent against GISTs resistant to both imatinib and sunitinib because of secondary mutations in the activation loop. |
| WOS关键词 | GASTROINTESTINAL STROMAL TUMORS ; C-KIT ; KINASE INHIBITOR ; ACQUIRED-RESISTANCE ; IMATINIB RESISTANCE ; HUMAN MASTOCYTOSIS ; TYROSINE KINASE ; WILD-TYPE ; MUTATIONS ; ACTIVATION |
| 资助项目 | National Natural Science Foundation of China[Y201181042] ; National Natural Science Foundation of China[81273546] ; National Science and Technology Major Project[2013ZX09102008] ; National Science and Technology Major Project[2013ZX09402102-001-004] |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000331129900015 |
| 出版者 | WILEY-BLACKWELL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277311]  |
| 专题 | 药理学第一研究室 |
| 通讯作者 | Lou, Liguang |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhao, Jie,Quan, Haitian,Xu, Yongping,et al. Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants[J]. CANCER SCIENCE,2014,105(1):117-125. |
| APA | Zhao, Jie,Quan, Haitian,Xu, Yongping,Kong, Xiangqian,Jin, Lu,&Lou, Liguang.(2014).Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants.CANCER SCIENCE,105(1),117-125. |
| MLA | Zhao, Jie,et al."Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants".CANCER SCIENCE 105.1(2014):117-125. |
入库方式： OAI收割
来源：上海药物研究所
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