The MET axis as a therapeutic target.
The MET axis as a therapeutic target.
复制标题
DOI：
10.1016/j.uct.2009.01.001
复制
发表时间：
2009-04-01
期刊：
影响因子：
--
通讯作者：
Salgia, Ravi
中科院分区：
文献类型：
--
作者：
Sattler, Martin;Salgia, Ravi
MET 受体酪氨酸激酶及其配体肝细胞生长因子 (HGF) 与多种恶性肿瘤的转化有关。 MET/HGF 通路的慢性或失调激活可能导致细胞生长、侵袭、血管生成和转移增加、细胞凋亡减少、细胞骨架功能改变和其他生物学变化。有人建议，配体激活的 MET 刺激足以实现表型的转化。此外，已鉴定出 MET 酪氨酸激酶结构域、近膜结构域或信号蛋白结构域内的扩增和激活突变（种系和/或体细胞）。 MET 功能获得性突变导致酪氨酸激酶活性失调或延长，这对其转化活性至关重要。许多针对配体依赖性激活或激酶结构域的治疗策略已被用来抑制 MET。将总结 MET 调节的信号事件激活和生物功能的不同结构要求。将描述治疗目标以及当前的临床前和临床方法。单独或与标准疗法联合靶向 HGF/MET 通路可能会改善 MET 依赖性恶性肿瘤的现有疗法。
The MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) have been implicated in transformation of a variety of malignancies. Chronic or dysregulated activation of the MET/HGF pathway may lead to increased cell growth, invasion, angiogenesis, and metastasis, reduced apoptosis, altered cytoskeletal functions and other biological changes. It has been suggested that ligand activated MET stimulation can be sufficient for a transforming phenotype. In addition, amplification and activation mutations (germline and/or somatic) within the tyrosine kinase domain, juxtamembrane domain, or semaphorin domain have been identified for MET. MET gain-of-function mutations lead to either deregulated or prolonged tyrosine kinase activity, which are instrumental to its transforming activity. A number of therapeutic strategies targeting ligand-dependent activation or the kinase domain have been employed to inhibit MET. The different structural requirements for activation of signaling events and biological functions regulated by MET will be summarized. Therapeutic targets and current pre-clinical and clinical approaches will be described. Targeting the HGF/MET pathway, alone or in combination with standard therapies, is likely to improve present therapies in MET-dependent malignancies.