慢性髓细胞白血病的酪氨酸激酶抑制剂耐药机制

近年,慢性髓细胞白血病(CML)的治疗方法不断取得进展,包括药物化疗、脾切除术、干扰素治疗、造血干细胞移植(HSCT)等方法.第一代酪氨酸激酶抑制剂(TKI)伊马替尼,可使CML患者的总体生存(OS)率与无事件生存(EFS)率均显著提高,已成为CML的一线治疗药物.然而,部分CML患者出现原发性或继发性TKI耐药,成为导致CML患者治疗失败的主要原因.探索TKI耐药机制、寻找应对TKI耐药的新策略成为CML相关研究热点.TKI耐药的机制复杂,与多种基因产物与细胞内信号分子相关,主要分为断裂点簇集区/Abelson白血病病毒(BCR/ABL)依赖途径与非BCR/ABL依赖途径,而这些耐药机制可以单独或同时存在于同一例CML患者.随着相关研究的深入,对CML患者TKI耐药机制的研究取得较大进展,笔者拟就相关研究进展进行综述.

Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia

In recent years,treatment of chronic myeloid leukemia(CML) keeps making progresses,which includes chemotherapy,splenectomy,interferon,hematopoietic stem cell transplantation (HSCT) and several other methods.The first generation of tyrosine kinase inhibitors (TKI) imatinib,which improved the overall survival (OS) and event free survival (EFS)rates of patients,has become the first-line treatment of CML.However,primary or secondary resistance to TKI has become the main cause of treatment failure in some CML patients.Exploring the mechanisms of drug resistance and searching for new strategies to deal with drug resistance have become a hot research topic in CML.The mechanisms of TKI resistance are complex,which relate to a variety of gene products and intracellular signaling molecules,and mainly divide into breakpoint cluster region/Abelson leukemia virus (BCR/ABL) dependent pathways and non-BCR/ABL dependent pathways.Some studies have found that these resistance mechanisms can exist alone or simultaneously in the same CML patient.With researches on the mechanisms of TKI resistance in CML patients have made great progress,the authors intend to make a brief overview of the research progress.