KIT mutations in GIST

被引:94
作者
Fletcher, Jonathan A.
Rubin, Brian P.
机构
[1] Brigham & Womens Hosp, Boston, MA 02115 USA
[2] Cleveland Clin Fdn, Dept Pathol Anat, Lerner Res Inst, Cleveland, OH 44195 USA
[3] Cleveland Clin Fdn, Dept Mol Genet, Lerner Res Inst, Cleveland, OH 44195 USA
[4] Cleveland Clin Fdn, Taussig Canc Ctr, Cleveland, OH 44195 USA
关键词
D O I
10.1016/j.gde.2006.12.010
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Most gastrointestinal stromal tumors (GISTs) contain oncogenic KIT or PDGFRA receptor tyrosine kinase mutations. These rare neoplasms are remarkably sensitive to the KIT and PDGFRA kinase inhibitors imatinib (also known as Gleevec) and sunitinib (Sutent), which have recently been approved as the standard therapeutic courses for patients with inoperable GIST. However, most GIST patients eventually develop clinical resistance to imatinib and sunitinib. Imatinib and sunitinib resistance generally result from secondary mutations in the KIT and/or PDGFRA kinase domains. Preclinical studies suggest that imatinib and sunitinib resistant mutations can be treated using more potent kinase inhibitors, such as nilotinib, which inactivate the mutant kinase proteins. Alternately, the mutant kinase proteins can be targeted using HSP90 inhibitors, which result in degradation of activated KIT and/or PDGFRA, or using KIT transcriptional repressors, such as flavopiridol.
引用
收藏
页码:3 / 7
页数:5
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