Targeting Bruton's Tyrosine Kinase Across B-Cell Malignancies
Targeting Bruton's Tyrosine Kinase Across B-Cell Malignancies
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DOI：
10.1007/s40265-018-1003-6
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发表时间：
2018-11-01
期刊：
影响因子：
11.5
通讯作者：
Niemann, Carsten Utoft
中科院分区：
文献类型：
--
作者：
da Cunha-Bang, Caspar;Niemann, Carsten Utoft
布鲁顿酪氨酸激酶（BTK）在B细胞发育和存活中至关重要。BTK作为B细胞受体（BCR）信号传导途径中的下游激酶的作用被充分描述。作为B细胞恶性肿瘤发病机制中的关键参与者，已经通过开发下游介质的抑制剂来探索失调的BCR信号传导的靶向。BTK的生物学功能的发现和用于临床使用的共价抑制剂的开发，作为主要药物的伊替尼和作为第二个临床批准的BTK抑制剂的acalabrutinib，彻底改变了B细胞恶性肿瘤的治疗选择。目前，伊布替尼获批用于套细胞淋巴瘤、慢性淋巴细胞白血病、淋巴浆细胞淋巴瘤/瓦尔登斯特伦巨球蛋白血症、小淋巴细胞淋巴瘤、边缘区淋巴瘤和慢性移植物抗宿主病，而acalabrutinib获批用于套细胞淋巴瘤。其他疾病适应症的潜在扩展正在几项临床试验中进行研究，而BTK抑制剂与化学免疫疗法或其他靶向药物的组合正在B细胞恶性肿瘤中进行系统性探索。
Bruton's tyrosine kinase (BTK) is crucial in B-cell development and survival. The role of BTK as a downstream kinase in the B-cell receptor (BCR) signaling pathway is well described. As a key player in the pathogenesis of B-cell malignancies, targeting of dysregulated BCR signaling has been explored by development of inhibitors of downstream mediators. Discovery of the biological function of BTK and the development of covalent inhibitors for clinical use, ibrutinib as the lead agent and acalabrutinib as the second clinically approved BTK inhibitor, have revolutionized the treatment options for B-cell malignancies. Currently, ibrutinib is approved for mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, small lymphocytic lymphoma, marginal zone lymphoma and chronic graft versus host disease, while acalabrutinib is approved for mantle cell lymphoma. Potential expansion of indications in other diseases is under investigation in several clinical trials, while combination of BTK inhibitors with either chemoimmunotherapy or other targeted agents is being systematically explored in B-cell malignancies.