Mutations within the activation loop of members of the class III receptor tyrosine kinase (RTK) subfamily, which includes KIT, PDGFRA, and FLT3, have been observed in multiple human tumor types. These mutations confer constitutive activation as well as resistance to the type II tyrosine kinase inhibitors (TKI) that are currently clinically available, such as imatinib and sunitinib. It is now understood that activation loop mutations in class III RTKs shift the activation state equilibrium away from inactive states, to which type II TKIs bind, to the active state by destabilizing the inactive conformation. Recently, type I TKIs, which can bind to active kinase conformations, have been developed with specificity for class III RTK members. Some type I TKIs, such as crenolanib and avapritinib (BLU-285), have entered clinical studies for patients with activation loop mutations in KIT, PDGFRA, or FLT3. Preliminary results suggest that these type I TKIs show activity in these patient populations that previously lacked effective treatments. This article reviews the inactive and active structures of KIT, PDGFRA, and FLT3, how the mutations seen in human cancers affect kinase structure, and the clinical implications of these mutations in terms of type I vs. type II TKI binding.

已经在多种人类肿瘤类型中观察到了包括KIT，PDGFRA和FLT3在内的III类受体酪氨酸激酶（RTK）亚家族成员激活环内的突变。这些突变赋予组成型激活以及对目前临床上可用的II型酪氨酸激酶抑制剂（TKI）（例如伊马替尼和舒尼替尼）的抵抗力。现在可以理解，通过破坏非活性构象的稳定性，III类RTK中的活化环突变使活化状态平衡从与II型TKIs结合的非活化状态转移至活化状态。最近，已经开发出可以结合活性激酶构象的I型TKI，其对III类RTK成员具有特异性。一些I型TKI，例如crenolanib和avapritinib（BLU-285），已进入针对KIT，PDGFRA或FLT3激活环突变的患者的临床研究。初步结果表明，这些I型TKI在以前缺乏有效治疗方法的这些患者人群中显示出活性。本文回顾了KIT，PDGFRA和FLT3的非活性和活性结构，在人类癌症中发现的突变如何影响激酶结构，以及这些突变在I型与II型TKI结合方面的临床意义。