Molecular and chromosomal mechanisms of resistance to imatinib (ST1571) therapy
Molecular and chromosomal mechanisms of resistance to imatinib (ST1571) therapy
复制标题
DOI：
10.1038/sj.leu.2402741
复制
发表时间：
2002-11-01
期刊：
影响因子：
11.4
通讯作者：
Hehlmann, R
中科院分区：
文献类型：
--
作者：
Hochhaus, A;Kreil, S;Hehlmann, R
伊马替尼选择性抑制bcr-abl酪氨酸激酶(STI571，Glivec/Gleevec)是治疗慢性粒细胞白血病(CML)的一种有前景的新策略。尽管有显著的血液学和细胞遗传学反应，耐药还是会发生，特别是在晚期疾病患者中。我们试图确定潜在的机制。慢性粒细胞白血病患者66例，其中髓系危象33例，淋巴系危象2例，加速期16例，慢性期13例，bcr-abl阳性急性淋巴细胞白血病2例，均对伊马替尼耐药。伊马替尼治疗的中位持续时间为148天(范围6-882天)。对患者进行了bcr-abl基因扩增、bcr-abl转录本的过度表达、克隆性核型进化和bcr-abl酪氨酸激酶结构域中伊马替尼结合位点突变的评估。结果如下：(1)耐药时bcr-abl转录本的中位数水平没有显著变化，但7/55例患者的bcr-abl水平增加了10倍；(2)荧光原位杂交检测到2/32例患者的bcr-abl基因扩增；(3)19/36例患者观察到额外的染色体异常；(4)23/66例患者检测到bcr-abl酪氨酸激酶结构域点突变，导致bcr-abl酪氨酸激酶的重新激活。总之，尽管伊马替尼耐药性的异质性发展具有挑战性，但BCR-ABL在许多耐药患者中活跃的事实表明，嵌合癌蛋白仍然是一个很好的治疗靶点。然而，克隆进化的患者更有可能具有BCR-ABL独立的耐药机制。这些观察结果证明了将伊马替尼与其他药物联合使用的试验。
Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (STI571, Glivec/Gleevec) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease. We sought to determine the underlying mechanisms. Sixty-six patients with CML in myeloid blast crisis (n=33), lymphoid blast crisis (n=2), accelerated phase (n=16), chronic phase (n=13), and BCR-ABL-positive acute lymphoblastic leukemia (n=2) resistant to imatinib were investigated. Median duration of imatinib therapy was 148 days (range 6-882). Patients were evaluated for genomic amplification of BCR-ABL, overexpression of BCR-ABL transcripts, clonal karyotypic evolution, and mutations of the imatinib binding site in the BCR-ABL tyrosine kinase domain. Results were as follows: (1) Median levels of BCR-ABL transcripts, were not significantly changed at the time of resistance but 7/55 patients showed a >10-fold increase in BCR-ABL levels; (2) genomic amplification of BCR-ABL was found in 2/32 patients evaluated by fluorescence in situ hybridization; (3) additional chromosomal aberrations were observed in 19/36 patients; (4) point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 23/66 patients. In conclusion, although the heterogeneous development of imatinib resistance is challenging, the fact that BCR-ABL is active in many resistant patients suggests that the chimeric oncoprotein remains a good therapeutic target. However, patients with clonal evolution are more likely to have BCR-ABL-independent mechanisms of resistance. The observations warrant trials combining imatinib with other agents.