The catalytic activity of Abl1 single and compound mutations: Implications for the mechanism of drug resistance mutations in chronic myeloid leukaemia
The catalytic activity of Abl1 single and compound mutations: Implications for the mechanism of drug resistance mutations in chronic myeloid leukaemia
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DOI：
10.1016/j.bbagen.2019.01.011
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发表时间：
2019-04-01
影响因子：
3
通讯作者：
Friedman, Ran
中科院分区：
文献类型：
--
作者：
Georgoulia, Panagiota S.;Todde, Guido;Friedman, Ran
背景：Abll是一种蛋白酪氨酸激酶，其突变引起的异常激活是几种癌症的罪魁祸首，最明显的是慢性髓性白血病。几种Abll抑制剂被用作抗癌药物。不幸的是，耐药性限制了它们的有效性。耐药的主要原因是Abll的激酶结构域（KD）在患者中发生突变。T315I突变对除ponatinib外的所有临床可用抑制剂具有耐药性。对波纳替尼的耐药性可通过复合（双）突变产生。方法：对Abll及其突变体的KD进行动力学测定，考察其催化活性。具体来说，考虑了导致对ponatinib耐药的突变体。用分子动力学模拟和多序列分析对实验结果进行了解释。结果：T315I泛抗性突变体的催化效率比原生KD低2倍以上。所有抗波纳替尼突变恢复酶的催化效率。其中两种（G250E/ T315I和Y253H/E255V）的催化效率是天然KD的5倍以上。结论：测量和分析表明，耐药至少部分是由于通过随后的突变产生了高效激酶。模拟强调了突变时Abll的两个结构重要区域，激活环和磷酸盐结合环的修饰。一般意义：实验和计算方法一起用于解释Abll激酶结构域的突变如何导致对目前用于治疗慢性髓性白血病的最先进药物的耐药性。
Background: Abll is a protein tyrosine kinase whose aberrant activation due to mutations is the culprit of several cancers, most notably chronic myeloid leukaemia. Several Abll inhibitors are used as anti-cancer drugs. Unfortunately, drug resistance limits their effectiveness. The main cause for drug resistance is mutations in the kinase domain (KD) of Abll that evolve in patients. The T315I mutation confers resistance against all clinically-available inhibitors except ponatinib. Resistance to ponatinib can develop by compound (double) mutations.Methods: Kinetic measurements of the KD of Abll and its mutants were carried out to examine their catalytic activity. Specifically, mutants that lead to drug resistance against ponatinib were considered. Molecular dynamics simulations and multiple sequence analysis were used for explanation of the experimental findings.Results: The catalytic efficiency of the T315I pan-resistance mutant is more than two times lower than that of the native KD. All ponatinib resistant mutations restore the catalytic efficiency of the enzyme. Two of them (G250E/ T315I and Y253H/E255V) have a catalytic efficiency that is more than five times that of the native KD.Conclusions: The measurements and analysis suggest that resistance is at least partially due to the development of a highly efficient kinase through subsequent mutations. The simulations highlight modifications in two structurally important regions of Abll, the activation and phosphate binding loops, upon mutations.General significance: Experimental and computational methods were used together to explain how mutations in the kinase domain of Abll lead to resistance against the most advanced drug currently in use to treat chronic myeloid leukaemia.