The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors;: kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations
The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors;: kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations
复制标题
DOI：
10.1182/blood.v99.5.1741
复制
发表时间：
2002-03-01
期刊：
影响因子：
20.3
通讯作者：
Longley, BJ
中科院分区：
文献类型：
--
作者：
Ma, YS;Zeng, S;Longley, BJ
引起KIT受体激酶自发激活的c-KIT突变与散发性成人肥大细胞增多症（SAHM）和人胃肠道间质瘤相关。我们将KIT激活突变分为“酶位点”型（EST）突变（影响激酶催化部分的结构）或“调节”型（FIT）突变（影响正常催化位点的调节）。使用表达野生型或突变型KIT的COS细胞，2种化合物STI 571和SU 9529在0.1至1 μ M时抑制野生型和RT突变型KIT，但即使在10 μ M时也不显著抑制与SAHM相关的Asp 816 VaI EST突变体。使用HMC 1肥大细胞系的2个亚克隆（均表达具有相同FIT突变的KIT，但不同之处在于其中一个还表达Asp 816 VaI EST突变），两种化合物均抑制RT突变体KIT，从而抑制仅FIT突变体细胞系中的增殖并产生细胞凋亡。这两种化合物都不能抑制Asp 816 VaI EST突变体KIT的活化，也不能产生细胞凋亡或显著抑制表达Asp 816 VaI突变的细胞系的增殖。这些研究表明，目前可用的KIT抑制剂可能是有用的，在治疗肿瘤细胞表达KIT激活其。天然配体或通过FIT激活突变如胃肠道间质瘤，但这两种化合物都不可能对SAHM有效。此外，这些结果有助于建立一个一般的，范例，从而影响致癌酶的RT或EST的突变分类可能是有用的，在预测肿瘤的敏感性或耐药性抑制药物。
Mutations of c-KIT causing spontaneous activation of the KIT receptor kinase are associated with sporadic adult human mastocytosis (SAHM) and with human gastrointestinal stromal tumors. We have classified KIT-activating mutations as either "enzymatic site" type (EST) mutations, affecting the structure of the catalytic portion of the kinase, or as "regulatory" type (FIT) mutations, affecting regulation of an otherwise normal catalytic site. Using COS cells expressing wild-type or mutant KIT, 2 compounds, STI571 and SU9529, Inhibited wild-type and RT mutant KIT at 0.1 to 1 muM but did not significantly inhibit the Asp816VaI EST mutant associated with SAHM, even at 10 muM. Using 2 subclones of the HMC1 mast cell line, which both express KIT with an identical FIT mutation but which differ in that one also expresses the Asp816VaI EST mutation, both compounds inhibited the RT mutant KIT, thereby suppressing proliferation and producing apoptosis in the FIT mutant-only cell line. Neither compound suppressed activation of Asp816VaI EST mutant KIT, and neither produced apoptosis or significantly suppressed proliferation of the cell line expressing the Asp816VaI mutation. These studies suggest that currently available KIT inhibitors may be useful in treating neoplastic cells expressing KIT activated by its. natural ligand or by FIT activating mutations such as gastrointestinal stromal tumors but that neither compound is likely to be effective against SAHM. Furthermore, these results help establish a general, paradigm whereby classification of mutations affecting oncogenic enzymes as RT or EST may be useful in predicting tumor sensitivity or resistance to inhibitory drugs.