Aix Marseille Université, INSERM, INRA, C2VN, Marseille, France.
Department of Respiratory Diseases-CHRU Montpellier, U1046 INSERM, UMR9214 CNRS University of Montpellier, Montpellier, France.
Pharmacol Ther. 2019 May;197:11-37. doi: 10.1016/j.pharmthera.2018.12.008. Epub 2018 Dec 14.
KIT is a receptor tyrosine kinase that after binding to its ligand stem cell factor activates signaling cascades linked to biological processes such as proliferation, differentiation, migration and cell survival. Based on studies performed on SCF and/or KIT mutant animals that presented anemia, sterility, and/or pigmentation disorders, KIT signaling was mainly considered to be involved in the regulation of hematopoiesis, gametogenesis, and melanogenesis. More recently, novel animal models and ameliorated cellular and molecular techniques have led to the discovery of a widen repertoire of tissue compartments and functions that are being modulated by KIT. This is the case for the lung, heart, nervous system, gastrointestinal tract, pancreas, kidney, liver, and bone. For this reason, the tyrosine kinase inhibitors that were originally developed for the treatment of hemato-oncological diseases are being currently investigated for the treatment of non-oncological disorders such as asthma, rheumatoid arthritis, and alzheimer's disease, among others. The beneficial effects of some of these tyrosine kinase inhibitors have been proven to depend on KIT inhibition. This review will focus on KIT expression and regulation in healthy and pathologic conditions other than cancer. Moreover, advances in the development of anti-KIT therapies, including tyrosine kinase inhibitors, and their application will be discussed.
KIT 是一种受体酪氨酸激酶，与配体干细胞因子结合后，激活与增殖、分化、迁移和细胞存活等生物学过程相关的信号级联。基于对出现贫血、不育和/或色素沉着障碍的 SCF 和/或 KIT 突变动物的研究，KIT 信号主要被认为参与造血、配子发生和黑色素生成的调节。最近，新的动物模型和改良的细胞和分子技术导致发现了 KIT 调节的更广泛的组织区室和功能。这种情况发生在肺、心脏、神经系统、胃肠道、胰腺、肾脏、肝脏和骨骼中。因此，最初为治疗血液肿瘤疾病而开发的酪氨酸激酶抑制剂目前正在研究用于治疗非肿瘤疾病，如哮喘、类风湿性关节炎和阿尔茨海默病等。其中一些酪氨酸激酶抑制剂的有益效果已被证明取决于 KIT 抑制。本综述将重点介绍 KIT 在癌症以外的健康和病理条件下的表达和调节。此外，还将讨论抗 KIT 治疗的进展，包括酪氨酸激酶抑制剂及其应用。
