摘要
SHP2(PTPN11基因编码的非受体型酪氨酸磷酸酶)通过调控生长因子/细胞因子受体调节信号转导过程从而维持细胞的增殖、分化、凋亡和存活。条件性敲入小鼠模型验证了PTPN11基因激活突变主要通过调节RTK信号通路如RASMAPK,PI3K-AKT,JAK-STAT来促进血液恶性肿瘤与实体肿瘤的发生。目前SHP2已经成为公认的恶性肿瘤治疗靶点,通过新型SHP2变构抑制剂阻断肿瘤生长具有临床应用前景。然而SHP2变构抑制剂单独或联合用药在针对特定肿瘤治疗过程中存在耐药性、非特异性和副作用等限制,更加有效的SHP2抑制剂的开发或联合用药策略的优化已成为关键问题。全文对SHP2在调控生长因子/细胞因子相关信号通路中发挥的作用及其激活突变导致恶性肿瘤发生的分子机制进行了总结,在此基础上综述了近年来SHP2抑制剂的开发和其用于治疗恶性肿瘤的临床进展。
SHP2(Non-receptor tyrosine phosphatase encoded by PTPN11)regulates signal transduction by regulating growth factor/cytokine receptors to maintain cell proliferation,differentiation,apoptosis,and survival.The conditional knock-in mouse models confirmed that PTPN11 activating mutation promotes the occurrence of hematologic malignancies and solid tumors by regulating RAS-MAPK,PI3K-AKT,and JAK-STAT signaling pathways.SHP2 has proved to be a target for the treatment of malignant tumors,which means that SHP2 allosteric inhibitors have clinical application prospects in blocking tumor growth.It should be noticed that treating specific tumors by SHP2 inhibitors alone or in combination with other targeted drugs has many limitations such as drug resistance,nonspecific,and toxicity.So,the optimization of SHP2 inhibitors and clinical combination strategy is crucial.This review summarizes the role of SHP2 in regulating growth factor/cytokine-related signaling pathways and the molecular mechanism of activating mutations leading to malignancies.Furthermore,the development of SHP2 inhibitors and their clinical progress in the treatment of malignant tumors are reviewed.
作者
孟欣怡
李杨
李圣珍
张佩
周丽莹
董磊
MENG Xinyi;LI Yang;LI Shengzhen;ZHANG Pei;ZHOU Liying;DONG Lei(Beijing Institute of Technology,Beijing,100081;Beijing Tide Pharmaceutical CO.,LTD,Beijing,100000)
出处
《生命科学仪器》
2022年第4期13-24,共12页
Life Science Instruments
基金
北京市自然科学基金重点研究专题项目(Z190018)《骨髓单细胞原位超分辨技术应用于白血病Shp2分子致病机理与快速临床诊断方法研究》
国家自然科学基金面上项目(81870123)《单核细胞中Ptpn11(Shp2)磷酸酶激活突变对正常造血干细胞在白血病发生中异常活化的研究》
作者简介
孟欣怡(1996-),女,硕士,E-mail:X1004382302@163.com;通信作者:董磊(1982-),男,博士,阿肯色大学,教授,E-mail:ldong@bit.edu.cn
