布鲁顿酪氨酸激酶抑制剂依鲁替尼治疗恶性肿瘤的作用机制

布鲁顿酪氨酸激酶(BTF)参与介导B细胞和巨噬细胞的多条信号通路,在其存活、增殖与分化过程中发挥重要作用,是治疗B细胞相关肿瘤和某些实体肿瘤新的分子靶标。依鲁替尼是首个口服不可逆BTK抑制剂,有效抑制B细胞的恶性增殖并诱导细胞凋亡。美国食品药品管理局现已批准用于套细胞淋巴瘤、慢性淋巴细胞白血病、华氏巨球蛋白血症、小淋巴细胞性淋巴瘤和边缘区淋巴瘤等B细胞相关肿瘤的临床治疗,现在进行的多项临床试验研究正在评估依鲁替尼对其他肿瘤适应证的拓展治疗作用。本文从布鲁顿酪氨酸激酶对下游信号通路的调控、依鲁替尼临床适应证的作用机制及耐药问题等方面进行综述。

Mechanisms of bruton tyrosine kinase inhibitor ibrutinib in treatment of malignancies

Bruton tyrosine kinase (BTK) is necessary in multiple signal transduction pathways mediating survival,proliferation,and differentiation of B lineage lymphoid cells and macrophages.BTK has emerged as a new molecular target for therapeutic intervention in human B-cell related malignancies and certain solid tumors.Ibrutinib is the first oral irreversible inhibitor of BTK,prevents the activation of pathways affected by BTK,and inhibits cell proliferation,and promotes apoptosis of cancer cells.Ibrutinib was granted an accelerated approval by the US Food and Drug Administration (FDA) for the treatment of patients with MCL,CLL,WM,SCL and MZL.Ongoing studies are evaluating ibrutinib in other types of tumors.This review summarized the mechanism of BTK modulating the activity of downstream signaling,clinical applications and drug resistance of ibrutinib.