Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107).
Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107).
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Bcr-Abl 耐药性筛查预测有限范围的点突变与 Abl 激酶抑制剂尼罗替尼 (AMN107) 的临床耐药性相关。
DOI：
10.1182/blood-2005-12-010132
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发表时间：
2005
期刊：
影响因子：
20.3
通讯作者：
J. Duyster
中科院分区：
文献类型：
--
作者：
N. von Bubnoff;P. Manley;J. Mestan;J. Sanger;C. Peschel;J. Duyster
在晚期慢性髓性白血病（CML）中，对甲磺酸伊马替尼的耐药性与BCR-ABL激酶结构域的点突变有关。新一代有效的ABL激酶抑制剂正在进行临床评估。重要的是生成这些化合物的特定耐药谱，这可以转化为组合和顺序治疗策略。在描述了尼罗替尼（AMN107）对一大组耐伊马替尼甲甲酰胺Bcr-Abl突变体的作用后，我们使用基于细胞的耐药性筛选研究了在尼罗替尼治疗下可能出现的突变体。与甲磺酸伊马替尼相反，对尼罗替尼的耐药与Bcr-Abl激酶突变的有限谱有关。其中包括影响p环和T315I的突变。在浓度为400 nM的尼罗替尼中，很少出现抗性菌落只表达T315I突变。除T315I外，当尼罗替尼浓度增加到2000 nM时，所鉴定的所有突变都被有效抑制，该浓度落在400 mg每日两次治疗患者血浆水平的峰谷范围内（3.6-1.7微米）。我们的研究结果表明，就耐药性的发展而言，尼罗替尼可能优于甲磺酸伊马替尼。然而，我们的研究表明，临床对尼洛替尼的耐药可能与T315I的主要出现有关。
In advanced-phase chronic myeloid leukemia (CML), resistance to imatinib mesylate is associated with point mutations in the BCR-ABL kinase domain. A new generation of potent ABL kinase inhibitors is undergoing clinical evaluation. It is important to generate specific resistance profiles for each of these compounds, which could translate into combinatorial and sequential treatment strategies. Having characterized nilotinib (AMN107) against a large panel of imatinib mesylate-resistant Bcr-Abl mutants, we investigated which mutants might arise under nilotinib therapy using a cell-based resistance screen. In contrast to imatinib mesylate, resistance to nilotinib was associated with a limited spectrum of Bcr-Abl kinase mutations. Among these were mutations affecting the P-loop and T315I. Rarely emerging resistant colonies at a concentration of 400 nM nilotinib exclusively expressed the T315I mutation. With the exception of T315I, all of the mutations that were identified were effectively suppressed when the nilotinib concentration was increased to 2000 nM, which falls within the peak-trough range in plasma levels (3.6-1.7 microM) measured in patients treated with 400 mg twice daily. Our findings suggest that nilotinib might be superior to imatinib mesylate in terms of the development of resistance. However, our study indicates that clinical resistance to nilotinib may be associated with the predominant emergence of T315I.
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吡啶并嘧啶型小分子激酶抑制剂对野生型和突变型 Bcr-Abl 的抑制。
影响因子：
11.2
作者：
vonBubnoff,Nikolas;Veach,DarrenR;Miller,WTodd;Li,Wanqing;Sänger,Jana;Peschel,Christian;Bornmann,WilliamG;Clarkson,Bayard;Duyster,Justus
通讯作者：
Duyster,Justus
影响因子：
50.3
作者：
Weisberg, E;Manley, PW;Griffin, JD
通讯作者：
Griffin, JD
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B
影响因子：
20.3
作者：
Bai, RY;Tao, OY;Duyster, J
通讯作者：
Duyster, J
影响因子：
56.9
作者：
Schindler, T;Bornmann, W;Kuriyan, J
通讯作者：
Kuriyan, J