伊马替尼治疗慢性粒细胞白血病的耐药机制与对策

Mechanism and strategy against Imatinib-resistant chronic myeloid leukemia

95%的慢性粒细胞白血病(chronic myeloid leukemia,CML)患者存在t(9;22)(q32;q21)易位即Ph'染色体,从而形成Bcr-Abl融合基因并编码具有高酪氨酸激酶活性的BCR-ABL融合蛋白,在慢性粒细胞白血病的发病中起着重要作用。甲磺酸伊马替尼(Imatinib mesylate,IM,格列卫)是针对酪氨酸激酶的靶向抑制剂,它通过与ATP竞争结合位点使底物不能磷酸化,从而阻断下游异常的细胞信号转导通路,达到抑制肿瘤细胞增殖并诱导细胞凋亡的目的,对慢性粒细胞白血病患者有很好的治愈率。但随着药物的推广,临床上部分病人出现了对伊马替尼的耐药。本文就伊马替尼耐药机制以及耐药患者的解决方案综述如下。

Philadelphia chromsome is found in 95% of chronic myeloid leukemia （CML） patients, which results from the reciprocal translocation of chromosome 9 and chromosome 22 and leads to the Bcr-Abl fusion gene. The BCR-ABL fusion product induces constitutively active cytoplasmic tyrosine kinase and plays a central role in the pathogenesis of the CML. A targeted tyrosine kinase inhibitor Imatinib mesylate（IM）, can inhibit tumor cell proliferation and induce its apoptosis by competing binding sites with ATP, blocking substrate phosphorylation, interrupting the abnormal cell signal transduction pathways. And IM shows a very good cure rate in CML patients. However, with the widely use of IM, some patients have appeared resistance. Here, we summarize the mechanisms of IM resistance and the corresponding solutions.