Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL
Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL
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DOI：
10.1016/s0092-8674(03)00190-9
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发表时间：
2003-03-21
期刊：
影响因子：
64.5
通讯作者：
Daley, GQ
中科院分区：
文献类型：
--
作者：
Azam, M;Latek, RR;Daley, GQ
Bcr - Abl融合蛋白激酶导致慢性髓性白血病，并且是信号转导抑制剂STI - 571/格列卫/伊马替尼（STI - 571）的作用靶点。对接受STI - 571化疗后复发的患者的BCR - ABL基因进行测序，发现了一组有限的激酶结构域突变，这些突变介导了耐药性。为了更全面地调查赋予STI - 571耐药性的氨基酸替代情况，我们对随机诱变的BCR - ABL进行了体外筛选，并发现了先前在患者中鉴定出的所有主要突变以及许多其他揭示获得性耐药新机制的突变。结构建模表明，一类新的变体通过变构作用破坏ABL激酶的自身抑制构象的稳定性，而STI - 571优先与这种自身抑制构象结合。这种筛选策略是一种适用于越来越多的靶向抗癌药物的范例，并提供了一种预测可能在临床上造成问题的耐药性氨基酸替代的方法。
The Bcr-Abl fusion protein kinase causes chronic myeloid leukemia and is targeted by the signal transduction inhibitor STI-571/Gleevec/imatinib (STI-571). Sequencing of the BCR-ABL gene in patients who have relapsed after STI-571 chemotherapy has revealed a limited set of kinase domain mutations that mediate drug resistance. To obtain a more comprehensive survey of the amino acid substitutions that confer STI-571 resistance, we performed an in vitro screen of randomly mutagenized BCR-ABL and recovered all of the major mutations previously identified in patients and numerous others that illuminate novel mechanisms of acquired drug resistance. Structural modeling implies that a novel class of variants acts allosterically to destabilize the autoinhibited conformation of the ABL kinase to which STI-571 preferentially binds' This screening strategy is a paradigm applicable to a growing list of target-directed anti-cancer agents and provides a means of anticipating the drug-resistant amino acid substitutions that are likely to be clinically problematic.