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摘要
慢性粒细胞白血病(CML)是一种骨髓增殖性肿瘤,表现为致病癌蛋白BCR-ABL1(断点簇区域/ Abelson激酶),这是一个具有本构酪氨酸激酶活性的融合蛋白。第一个酪氨酸激酶抑制剂(TKI)——¬¬¬伊马替尼彻底改变了慢性粒细胞白血病的治疗。尽管伊马替尼的效果惊人,但原发性和获得性耐药以及伊马替尼不耐受的影响仍然存在。BCR-ABL1点突变, BCR-ABL1基因的扩增和流出药物转运增加的表达的机制,这些在抵抗中起着重要的作用,已被广泛地描述。因此,第二代和第三代的TKI已被研究去克服抵抗。然而,一些CML患者用所有可用的TKI都难以治疗。此外,大多数患者中断TKI治疗后复发由于CML干细胞的存在,这种干细胞已被证明主要耐受TKIs。因此,TKI本身不足以治愈慢性粒细胞白血病,并且有必要进一步研究分子耐药机制在CML干细胞和体细胞中来确定新目标来克服抵抗和消除残余CML干细胞。本文综述CML的各种分子耐药机制的新见解,并讨论了基于目标的治疗靶标,这些靶标最近被发现在耐药性的分子机制发挥重要作用。
关键词: 慢性粒细胞白血病、机制、抵抗、战略、酪氨酸激酶抑制剂、目标疗法。
Current Cancer Drug Targets
Title:New Insights into the Molecular Resistance Mechanisms of Chronic Myeloid Leukemia
Volume: 16 Issue: 4
Author(s): Rui Huang, Qian Kang, Huimin Liu, Yuhua Li
Affiliation:
关键词: 慢性粒细胞白血病、机制、抵抗、战略、酪氨酸激酶抑制剂、目标疗法。
摘要: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the causative oncoprotein BCR-ABL1 (Breakpoint-cluster region/Abelson kinase), which is a fusion protein with constitutive tyrosine kinase activity. The first tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of CML. Despite the spectacular effects of imatinib, primary and acquired resistance as well as intolerance to imatinib still exist. The mechanisms of BCR-ABL1 point mutations, amplification of the BCR-ABL1 gene and increased expression of efflux drug transporters, which play important roles in resistance, have been extensively described. Consequently, second- and third-generation TKIs have been explored to overcome resistance. However, some CML patients are refractory to all available TKIs. In addition, most patients relapse after discontinuing TKI therapy, due to the existence of CML stem cells, which have been demonstrated to be primarily resistant to TKIs. Thus, TKIs alone are not sufficient to cure CML, and it is necessary to further investigate the molecular resistance mechanisms in both the bulk and stem cells of CML to identify new targets to overcome resistance and eradicate the residual CML stem cells. This article reviews new insights into the various molecular resistance mechanisms of CML and discusses treatment strategies based on the targets that have recently been found to play an important role in the molecular mechanisms of resistance.
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Cite this article as:
Rui Huang, Qian Kang, Huimin Liu, Yuhua Li , New Insights into the Molecular Resistance Mechanisms of Chronic Myeloid Leukemia, Current Cancer Drug Targets 2016; 16 (4) . https://dx.doi.org/10.2174/1568009615666150921141004
DOI https://dx.doi.org/10.2174/1568009615666150921141004 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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