慢性髓系白血病患者酪氨酸激酶抑制剂耐药机制的研究进展

Advances in the Mechanism of Tyrosine Kinase Inhibitors Resistance in Patients with Chronic Myeloid Leukemia

慢性髓系白血病(CML)是一种起源于造血系统的恶性肿瘤,以费城染色体和Bcr-Abl融合基因为标志。酪氨酸激酶抑制剂(TKIs)是一种靶向治疗药物,可抑制酪氨酸激酶的活性,使CML患者获得缓解,延长CML患者的总生存期和无进展生存期,但仍有部分患者在TKIs治疗期间出现原发性或继发性耐药,导致治疗失败。CML患者的耐药机制较复杂,可依赖于Bcr-Abl途径,主要包括激酶位点突变、基因扩增、DNA修复缺陷及基因组的不稳定性等;也可不依赖于Bcr-Abl途径,主要包括替代信号通路的激活、白血病干细胞、骨髓微环境等。因此,了解CML的TKIs耐药机制对CML的治疗尤为重要。

Chronic myeloid leukemia(CML)is a malignancy that originates in the hematopoietic system,marked by the Philadelphia chromosome and the Bcr-Abl fusion gene.Tyrosine kinase inhibitors(TKIs)are a kind of targeted therapeutic drug that inhibit tyrosine kinase activity,which can prolong the overall survival and progression-free survival of CML patients,but there are still some patients who have primary or secondary resistance during TKIs treatment,resulting in treatment failure.The resistance mechanism is more complex,through the Bcr-Abl dependant pathway,mainly including kinase site mutations,gene amplification,DNA repair defects and genomic instability,or the Bcr-Abl independent pathway,mainly including the activation of alternative signaling pathways,leukemia stem cells,bone marrow microenvironment,etc.Therefore,it is particularly important to understand the mechanism of TKIs resistance in CML for the treatment of CML.