ALK 突变结合 TKI
中文名称
通路描述
活化的 ALK 形式的异常信号可通过酪氨酸激酶抑制剂（TKI）抑制。ALK 与其他酪氨酸激酶受体类似，通过一系列磷酸化和构象变化激活，使受体从无活性形式转变为完全激活形式。类型 II TKI 在受体 ATP 结合槽相邻处结合无活性形式，而类型 I TKI 结合活性形式（综述见 Roskoski, 2013）。类型 I 抑制剂（crizotinib, brigatinib, alectinib, ceritinib 和 lorlatinib）均获批用于治疗 ALK 依赖性癌症。然而，对 TKI 的耐药性并不罕见，要么通过获得次级突变，要么通过激活绕过 ALK 信号依赖的通路（综述见 Lovly and Pao, 2012; Lin et al, 2017; Della Corte et al, 2018）。
英文描述
ALK mutants bind TKIs Aberrant signaling by activated forms of ALK can be inhibited by tyrosine kinase inhibitors (TKIs). ALK, like other tyrosine kinase receptors, is activated through a series of phosphorylation and conformational changes that move the receptor from the inactive form to the fully activated form. Type II TKIs bind to the inactive form of the receptor at a site adjacent to the ATP-binding cleft, while type I TKIs bind to the active form (reviewed in Roskoski, 2013). Type I inhibitors crizotinib, brigatinib, alectinib, ceritinib and lorlatinib are all approved for treatment of ALK-dependent cancer. Development of resistance to TKIs is not uncommon, however, either through acquisition of secondary mutations or through activation of bypass pathways that remove the dependence on ALK signaling (reviewed in Lovly and Pao, 2012; Lin et al, 2017; Della Corte et al, 2018).
所含基因
1 个基因