Resistance in the land of molecular cancer therapeutics
Resistance in the land of molecular cancer therapeutics
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DOI：
10.1016/s1535-6108(02)00101-0
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发表时间：
2002-08-01
期刊：
影响因子：
50.3
通讯作者：
Shannon, KM
中科院分区：
文献类型：
--
作者：
Shannon, KM
融合酪氨酸激酶Bcr-Abl在慢性粒细胞白血病（CML）的发病机制中起重要作用。伊马替尼是一种有效的Bcr-Abl抑制剂，在CML患者中显示出令人印象深刻的临床活性。然而，原发性和获得性耐药发生在许多患者中，并且与原发性白血病细胞中Bcr-Abl的再活化有关。在过去一年中报道的研究已经开始阐明伊马替尼耐药的分子基础，这可能涉及BCR-ABL的扩增，或者更常见的是，将氨基酸取代引入Bcr-Abl激酶的突变。生化分析和分子建模表明，这些突变蛋白保留激酶活性，但由于结构变化，扰乱药物结合抑制不太敏感。这些研究为阐明靶向治疗的耐药性建立了范例。
The fusion tyrosine kinase Bcr-Abl plays a fundamental role in the pathogenesis of chronic myeloid leukemia (CML). Imatinib, a potent inhibitor of Bcr-Abl, has shown impressive clinical activity in CML patients. However, primary and acquired resistance occurs in many patients and is associated with reactivation of Bcr-Abl in primary leukemia cells. Studies reported over the past year have begun to elucidate the molecular basis of imatinib resistance, which may involve amplification of BCR-ABL or, more commonly, mutations that introduce amino acid substitutions into the Bcr-Abl kinase. Biochemical analysis and molecular modeling indicate that these mutant proteins retain kinase activity but are less sensitive to inhibition due to structural changes that perturb drug binding. These studies establish a paradigm for elucidating resistance to targeted therapeutics.