SHP2调节剂在肿瘤免疫治疗中的研究进展  

Advances of SHP2 modulators in the cancer immunotherapy

作　　者：杨欣语 尚佳文 于海云 宋宜辉 余斌[1,2] YANG Xin-yu;SHANG Jia-wen;YU Hai-yun;SONG Yi-hui;YU Bin(School and Institute of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001,China;Key Laboratory of Advanced Drug Preparation Technologies,Zhengzhou 450001,China)

机构地区：[1]郑州大学药学院药物研究院,河南郑州450001 [2]药物关键制备技术教育部重点实验室,河南郑州450001

出　　处：《药学学报》2023年第8期2226-2238,共13页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(31900875);河南省优势学科培育联合基金(22610013);教育部“春晖计划”合作科研项目(HZKY20220280);郑州大学大学生创新创业训练计划项目(2023CXCY711).

摘　　要：Src同源酪氨酸磷酸酶2(Src homology phosphotyrosyl phosphatase 2,SHP2)是由PTPN11编码的蛋白酪氨酸磷酸酶,可催化蛋白酪氨酸位点的去磷酸化。作为汇聚节点,SHP2介导鼠肉瘤(rat sarcoma,RAS)-快速加速纤维肉瘤(rapidly accelerated fibrosarcoma,RAF)-丝裂原活化细胞外信号调节激酶(mitogen-activated extracellular signal-regulated kinase,MEK)-细胞外调节蛋白激酶(extracellular regulated protein kinases,ERK)、磷脂酰肌醇-3-激酶(phosphatidylinositol 3-kinase,PI3K)-丝氨酸/苏氨酸蛋白激酶(serine/threonine kinase,AKT)、Janus激酶(janus kinase,JAK)-信号转导和转录激活因子(signal transducer and activator of transcription,STAT)和程序性死亡受体1(programmed death-1,PD-1)/程序性死亡受体-配体1(programmed cell death-ligand 1,PD-L1)等多个信号通路,不仅可调控肿瘤细胞的生长增殖,还可通过影响肿瘤微环境介导肿瘤细胞的免疫逃逸,在肿瘤免疫调控中发挥双重生物学功能,是一种很有前景的肿瘤免疫治疗靶点。截止目前,已有多种SHP2变构抑制剂开展了单一或联合用药策略的肿瘤免疫治疗临床研究,此外SHP2激活剂也在肿瘤免疫调控领域呈现出治疗潜力。本文综述了SHP2在肿瘤细胞和免疫细胞中的双重肿瘤免疫调控功能,概述了目前SHP2调节剂在肿瘤免疫治疗领域的最新研究进展,并对该领域的研究挑战和应用前景进行了讨论和展望,旨在开拓SHP2调节剂在肿瘤免疫治疗领域的新视野。Src homology phosphotyrosyl phosphatase 2(SHP2)is a protein tyrosine phosphatase encoded by PTPN11,which catalyzes the dephosphorylation of protein tyrosine.As a convergence node,SHP2 mediates multiple signaling pathways such as rat sarcoma(RAS)-rapidly accelerated fibrosarcoma(RAF)-mitogen-activated extracellular signal-regulated kinase(MEK)-extracellular regulated protein kinases(ERK),phosphatidylinositol 3-kinase(PI3K)-serine/threonine kinase(AKT),janus kinase(JAK)-signal transducer and activator of transcription(STAT)and programmed death-1(PD-1)/programmed cell death-ligand 1(PD-L1).It can not only regulate the growth and proliferation of tumor cells,but also mediate the immune escape of tumor cells by influencing the tumor microenvironment.Given its dual biological functions in tumor immune regulation,SHP2 is a promising target for cancer immunotherapy.To date,several SHP2 allosteric inhibitors have been advanced into clinical trials for tumor immunotherapy with single or combination therapeutic strategies.Additionally,SHP2 activators also showed therapeutic potential in the field of tumor immune modulation.In this paper,we reviewed the dual function of SHP2 in both tumor and immune cells.Besides,the challenges and prospects of SHP2 modulators in cancer immunotherapy were also briefly discussed,aiming to explore new horizon of SHP2 modulators for tumor immunotherapy.

关 键 词：蛋白质磷酸化 蛋白酪氨酸磷酸酶 SHP2 肿瘤免疫调控 SHP2调节剂 

分 类 号：R915[医药卫生—微生物与生化药学]