Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia
Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia
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DOI：
10.1158/1078-0432.ccr-09-1068
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发表时间：
2009-12-15
影响因子：
11.5
通讯作者：
Apperley, Jane
中科院分区：
文献类型：
--
作者：
Milojkovic, Dragana;Apperley, Jane
选择性酪氨酸激酶抑制剂（TKI）形式的靶向治疗已经改变了慢性粒细胞白血病（CIVIL）的管理方法，并显着改善了患者的预后，以至于伊马替尼目前被接受为几乎所有CIVIL患者的一线药物，无论疾病的分期如何。在大多数慢性期患者中获得了令人印象深刻的临床应答;然而，并非所有患者都对伊马替尼产生了最佳应答，此外，许多患者的临床应答不会持续。白血病细胞证明对TKI耐药和BCR-ABL 1信号转导从先前抑制恢复的过程，引发了对耐药的因果机制和克服治疗干预耐药的策略的追求。ABL激酶结构域突变已广泛涉及TKI耐药的发病机制，然而，越来越明显的是，突变的存在并不能解释所有耐药病例，也不能解释TKI未能消除最佳应答患者的微小残留疾病。探索TKI耐药性的重点已经扩展到包括药物递送至其靶点的机制以及药物流入和流出蛋白对TKI生物利用度的影响。伊马替尼的局限性激发了第二代TKI的开发，以克服对这种主要疗法的耐药性的影响。(Clin Cancer Res 2009;15（24）：7519-27）
Targeted therapy in the form of selective tyrosine kinase inhibitors (TKI) has transformed the approach to management of chronic myeloid leukemia (CIVIL) and dramatically improved patient outcome to the extent that imatinib is currently accepted as the first-line agent for nearly all patients presenting with CIVIL, regardless of the phase of the disease. Impressive clinical responses are obtained in the majority of patients in chronic phase; however, not all patients experience an optimal response to imatinib, and furthermore, the clinical response in a number of patients will not be sustained. The process by which the leukemic cells prove resistant to TKIs and the restoration of BCR-ABL1 signal transduction from previous inhibition has initiated the pursuit for the causal mechanisms of resistance and strategies by which to surmount resistance to therapeutic intervention. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance, however, it is increasingly evident that the presence of mutations does not explain all cases of resistance and does not account for the failure of TKIs to eliminate minimal residual disease in patients who respond optimally. The focus of exploring TKI resistance has expanded to include the mechanism by which the drug is delivered to its target and the impact of drug influx and efflux proteins on TKI bioavailability. The limitations of imatinib have inspired the development of second generation TKIs in order to overcome the effect of resistance to this primary therapy. (Clin Cancer Res 2009;15(24):7519-27)