BTK抑制剂在慢性淋巴细胞白血病中的作用机制及应用进展

Action Mechanism and Application Progress of Bruton Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia

布鲁顿酪氨酸激酶(BTK)是一种非受体酪氨酸激酶,在正常和恶性B淋巴细胞中的B细胞受体(BCR)信号转导中起核心作用。在包括慢性淋巴细胞白血病(CLL)在内的B细胞淋巴肿瘤中,BCR信号通路的活化促进肿瘤细胞的生存和增殖。近年来,以伊布替尼为代表的一系列BTK抑制剂(BTKi)逐渐取代了免疫化疗,成为CLL治疗的中坚药物。共价BTKi不仅影响肿瘤细胞本身,还通过重构肿瘤微环境,促使CLL细胞凋亡;全新的非共价BTKi在临床试验中也展现出了良好的治疗效果和安全性,为克服共价BTKi应用中出现的耐药和不耐受带来了新的希望。综述BTKi在CLL中的作用机制及应用进展,以期为BTKi的基础研究和临床应用提供参考。

Bruton tyrosine kinase(BTK) is a nonreceptor tyrosine kinase playing a key role in B cell antigen receptor(BCR) signal transduction. Activation of BCR signaling pathway is involved in the pathogenesis of multiple B cell malignancies, including chronic lymphocytic leukemia(CLL). In recent years, the application of covalent BTK inhibitors(BTKi) such as ibrutinib, has revolutionized the treatment of CLL. BTKi target tumor cells as well as microenvironment to induce apoptosis. Novel non-covalent BTKi has shown promising efficacy and safety profile, which may overcome drug resistance and intolerability of classic covalent BTKi. In this review, we discussed the mechanisms and clinical studies of both covalent and non-covalent BTKi in CLL so as to provide reference for basic research and clinical application of BTKi.