Anticipating clinical resistance to target-directed agents - The BCR-ABL paradigm
Anticipating clinical resistance to target-directed agents - The BCR-ABL paradigm
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DOI：
10.1007/bf03256446
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发表时间：
2006-01-01
影响因子：
4
通讯作者：
Daley, George Q.
中科院分区：
文献类型：
--
作者：
Azam, Mohammad;Daley, George Q.
BCR-ABL的失调酪氨酸激酶活性是必要的，足以诱导慢性粒细胞性白血病（CML）。该观察结果为特异性针对BCR-ABL蛋白激酶活性的小分子抑制剂的发展铺平了道路。确实，伊马替尼的惊人成功彻底改变了目标癌症治疗的整个领域。然而，临床抵抗的发展使对伊马替尼的惊人功效的热情得到了缓解。在本质上，在所有情况下，抗性是由激酶结构域突变和/或BCR-ABL基因过表达引起的。为了克服耐药性，已经开发了几种新型的BCR-ABL抑制剂，并且正在临床试验中，尽管不可避免地会出现对第二代抑制剂的抗性。尽管如此，激酶代表了几种疾病治疗干预的有吸引力的靶标，目前，大约50种不同的激酶抑制剂正在临床试验中。我们预计对这些化合物的耐药性将遵循与伊马替尼观察到的机制相似的机制。电阻突变通过直接定位对药物结合的障碍或变构调节激酶动力学会导致其作用。这篇综述强调了这两个不同类别的主要机制以赋予耐药性。
The deregulated tyrosine kinase activity of BCR-ABL is necessary and sufficient to induce chronic myelogenous leukemia (CML). This observation has paved the way for the development of small-molecule inhibitors specifically targeting the kinase activity of the BCR-ABL protein. Indeed, the amazing success of imatinib has revolutionized the whole area of targeted cancer therapeutics. However, enthusiasm for the striking efficacy of imatinib has been tempered by the development of clinical resistance. In essentially all cases, resistance results from kinase domain mutations and/or overexpression of the BCR-ABL gene. To overcome resistance, several novel BCR-ABL inhibitors have been developed and are in clinical trials, though it is inevitable that resistance to second-generation inhibitors will occur as well. Nonetheless, kinases represent an attractive target for therapeutic intervention in several diseases and, at present, some 50 different kinase inhibitors are in clinical trials. We anticipate that resistance to these compounds will follow mechanisms similar to those observed with imatinib. Resistance mutations cause their effect either by direct steric hindrance to drug binding or by allosterically modulating kinase dynamics. This review highlights the principal mechanisms underlying point mutations from these two different classes to confer drug resistance.