文章：

第二代BCR-ABL抑制剂用于治疗伊马替尼耐药慢性髓性白血病

Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia

原文发布日期：2007-05-01

DOI: 10.1038/nrc2126

类型: Review Article

开放获取: 否

要点：

1. The structural basis for imatinib resistance in chronic myeloid leukaemia (CML) involves the emergence of imatinib-resistant BCR-ABL point mutations; mutations are usually those that impair drug binding.
2. More than 50 different BCR-ABL mutations have been identified in patients with imatinib-resistant CML and through random mutagenesis assays.
3. Different imatinib-resistant BCR-ABL point mutants can have different transforming potentials in cells and different prognostic outcomes.
4. Methods to predict imatinib-resistant BCR-ABL mutants include PCR-based screening assays, such as the highly sensitive allele-specific oligonucleoside (ASO)-PCR method, and the denaturing high-performance liquid chromatography (D-HPLC)-based assay.
5. Imatinib-resistant BCR-ABL point mutations have been found to pre-exist in newly diagnosed patients with CML, as well as be acquired owing to selective pressure of imatinib. Furthermore, imatinib fails to deplete leukaemic stem cells.
6. New BCR-ABL inhibitors in clinical trials include ABL inhibitors (nilotinib), dual Src family and ABL kinase inhibitors (bosutinib, INNO-404 and AZD0530), non-ATP competitive inhibitors of BCR-ABL (ON012380) and Aurora kinase inhibitors (MK-0457 and PHA-739358). The dual Src and ABL inhibitor dasatinib has recently been approved by the US Food and Drug Administration for the treatment of patients with CML or Philadelphia chromosome positive acute lymphoblastic leukaemia resistant or intolerant to imatinib.
7. BCR-ABL point mutants resistant to the second generation inhibitors nilotinib and dasatinib have been identified through cell-based resistance screens.
8. Strategies to circumvent the emergence of resistance include combination therapy using inhibitors of BCR-ABL and other targets.

要点翻译：

1. 伊马替尼在慢性髓系白血病（CML）中产生耐药性的结构基础涉及伊马替尼耐药性BCR-ABL点突变的出现；这些突变通常会影响药物结合。
2. 通过对伊马替尼耐药CML患者的研究及随机诱变实验，已鉴定出50多种不同的BCR-ABL突变。
3. 不同的伊马替尼耐药BCR-ABL点突变在细胞中可能具有不同的转化潜能和预后结果。
4. 预测伊马替尼耐药BCR-ABL突变的方法包括基于PCR的筛选检测，如高灵敏度等位基因特异性寡核苷酸（ASO）-PCR法，以及基于变性高效液相色谱（D-HPLC）的检测。
5. 研究发现，伊马替尼耐药BCR-ABL点突变既存在于新诊断的CML患者中，也可因伊马替尼的选择压力而获得。此外，伊马替尼无法清除白血病干细胞。
6. 临床试验中的新型BCR-ABL抑制剂包括ABL抑制剂（尼洛替尼）、双重Src家族和ABL激酶抑制剂（博舒替尼、INNO-404和AZD0530）、非ATP竞争性BCR-ABL抑制剂（ON012380）及极光激酶抑制剂（MK-0457和PHA-739358）。双重Src和ABL抑制剂达沙替尼近期已获美国食品药品监督管理局批准，用于治疗对伊马替尼耐药或不耐受的CML或费城染色体阳性急性淋巴细胞白血病患者。
7. 通过基于细胞的耐药性筛选，已鉴定出对第二代抑制剂尼洛替尼和达沙替尼耐药的BCR-ABL点突变。
8. 规避耐药性出现的策略包括联合使用BCR-ABL抑制剂与其他靶点抑制剂进行治疗。

英文摘要：

Imatinib, a small-molecule ABL kinase inhibitor, is a highly effective therapy for early-phase chronic myeloid leukaemia (CML), which has constitutively active ABL kinase activity owing to the expression of the BCR-ABL fusion protein. However, there is a high relapse rate among advanced- and blast-crisis-phase patients owing to the development of mutations in the ABL kinase domain that cause drug resistance. Several second-generation ABL kinase inhibitors have been or are being developed for the treatment of imatinib-resistant CML. Here, we describe the mechanism of action of imatinib in CML, the structural basis of imatinib resistance, and the potential of second-generation BCR-ABL inhibitors to circumvent resistance.

摘要翻译： 

伊马替尼是一种小分子ABL激酶抑制剂，对早期慢性髓性白血病（CML）具有显著疗效，该病由于BCR-ABL融合蛋白的表达导致ABL激酶持续活化。然而，晚期和急变期患者因ABL激酶结构域发生突变而产生耐药性，复发率较高。目前已开发出多种第二代ABL激酶抑制剂用于治疗伊马替尼耐药的CML。本文阐述了伊马替尼在CML中的作用机制、耐药性的结构基础，以及第二代BCR-ABL抑制剂克服耐药性的潜力。

原文链接：

Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia