Walz Christoph, Sattler Martin
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Crit Rev Oncol Hematol. 2006 Feb;57(2):145-64. doi: 10.1016/j.critrevonc.2005.06.007. Epub 2005 Oct 5.
Imatinib mesylate (Gleevec) was developed as the first molecularly targeted therapy that specifically inhibits the BCR-ABL tyrosine kinase activity in patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML). Due to its excellent hematologic and cytogenetic responses, particularly in patients with chronic phase CML, imatinib has moved towards first-line treatment for newly diagnosed CML. Nevertheless, resistance to the drug has been frequently reported and is attributed to the fact that transformation of hematopoietic stem cells by BCR-ABL is associated with genomic instability. Point mutations within the ABL tyrosine kinase of the BCR-ABL oncoprotein are the major cause of resistance, though overexpression of the BCR-ABL protein and novel acquired cytogenetic aberrations have also been reported. A variety of strategies derived from structural studies of the ABL-imatinib complex have been developed, resulting in the design of novel ABL inhibitors, including AMN107, BMS-354825, ON012380 and others. The major goal of these efforts is to create new drugs that are more potent than imatinib and/or more effective against imatinib-resistant BCR-ABL clones. Some of these drugs have already been successfully tested in preclinical studies where they show promising results. Additional approaches are geared towards targeting the expression or stability of the BCR-ABL kinase itself or targeting signaling pathways that are chronically activated and required for transformation. In this review, we will discuss the underlying mechanisms of resistance to imatinib and novel targeted approaches to overcome imatinib resistance in CML.
甲磺酸伊马替尼（格列卫）是作为首个分子靶向疗法开发的，它能特异性抑制费城染色体阳性（Ph+）慢性髓性白血病（CML）患者体内的BCR-ABL酪氨酸激酶活性。由于其出色的血液学和细胞遗传学反应，尤其是在慢性期CML患者中，伊马替尼已成为新诊断CML的一线治疗药物。然而，对该药的耐药性屡有报道，这归因于BCR-ABL对造血干细胞的转化与基因组不稳定有关。BCR-ABL癌蛋白的ABL酪氨酸激酶内的点突变是耐药的主要原因，不过也有报道称BCR-ABL蛋白的过表达和新出现的获得性细胞遗传学畸变。基于ABL-伊马替尼复合物结构研究的多种策略已被开发出来，从而设计出了新型ABL抑制剂，包括AMN107、BMS-354825、ON012380等。这些努力的主要目标是研发出比伊马替尼更有效和/或对伊马替尼耐药的BCR-ABL克隆更有效的新药。其中一些药物已在临床前研究中成功测试，显示出有前景的结果。其他方法则旨在靶向BCR-ABL激酶本身的表达或稳定性，或靶向那些长期激活且对转化至关重要的信号通路。在本综述中，我们将讨论伊马替尼耐药的潜在机制以及克服CML中伊马替尼耐药的新型靶向方法。
