Resistance to targeted therapy in chronic myelogenous leukemia
Resistance to targeted therapy in chronic myelogenous leukemia
复制标题
DOI：
10.1053/j.seminhematol.2006.12.002
复制
发表时间：
2007-01-01
影响因子：
3.6
通讯作者：
Mueller, Martin C.
中科院分区：
文献类型：
--
作者：
Hochhaus, Andreas;Erben, Philipp;Mueller, Martin C.
Bcr-Abl选择性酪氨酸激酶抑制剂甲磺酸伊马替尼（格列卫，格列卫，诺华，东汉诺威，新泽西州）的出现已经大大改变了慢性髓细胞性白血病（CML）的治疗前景。然而，一些患者，主要是那些晚期疾病，要么最初难治伊马替尼或最终发展伊马替尼耐药。伊马替尼耐药或不耐受通常取决于Bcr-Abl激酶活性的重新出现，但也可能表明Bcr-Abl非依赖性疾病进展。II/III期试验的结果表明，耐药率和复发率与疾病分期和监测参数（血液学、细胞遗传学和分子学缓解）相关。迄今为止，已经从伊马替尼耐药患者中分离出40多种不同的点突变，这些点突变编码Bcr-Abl激酶结构域中不同的单个氨基酸取代。这些突变会影响伊马替尼结合或Bcr-Abl激酶结构域调控区中的氨基酸，导致对伊马替尼敏感性降低，同时保留异常的激酶活性。早期突变检测可能有助于风险分层和基于分子的治疗决策。为了克服伊马替尼耐药疾病，最近开发了具有针对伊马替尼耐药突变的活性和/或具有替代途径（例如Src活化）的抑制的新型酪氨酸激酶抑制剂。其他策略包括伊马替尼剂量递增、联合治疗和治疗中断，以停止耐药细胞的克隆选择。
The advent of the Bcr-Abl selective tyrosine kinase inhibitor imatinib mesylate (Glivec, Gleevec, Novartis, East Hanover, NJ) has substantially changed the treatment landscape for chronic myelogenous leukemia (CML). However, some patients, primarily those with advanced disease, are either initially refractory to imatinib or eventually develop imatinib resistance. Imatinib resistance or intolerance frequently depends on the re-emergence of Bcr-Abl kinase activity, but can also indicate Bcr-Abl-independent disease progression. Results from phase II/III trials suggest rates of resistance and relapse correlate with stage of disease and with the monitoring parameters: hematologic, cytogenetic, and molecular responses. To date, more than 40 different point mutations that code for distinct single amino acid substitutions in the Bcr-Abl kinase domain have been isolated from imatinib-resistant patients. These mutations affect amino acids involved in imatinib binding or in regulatory regions of the Bcr-Abl kinase domain, resulting in decreased sensitivity to imatinib while retaining aberrant kinase activity. Early mutation detection may aid in risk stratification and molecular-based treatment decisions. To overcome imatinib-resistant disease, novel tyrosine kinase inhibitors with activity against imatinib-resistant mutations and/or with inhibition of alternative pathways, such as Src activation, have recently been developed. Additional strategies include imatinib dose escalation, combination therapy, and treatment interruption to stop clonal selection of resistant cells.