靶向血小板衍生生长因子受体A（PDGFRA）-含Src同源2结构域蛋白酪氨酸磷酸酶2（SHP2）信号通路可增强异柠檬酸脱氢酶1（IDH1）突变型胶质瘤的放射治疗效果。

Targeting PDGFRA-SHP2 Signaling Enhances Radiotherapy in IDH1-Mutant Glioma.

作者信息

Yu Xiaozhou, Song Xiao, Tiek Deanna, Wu Runxin, Walker Maya, Horbinski Craig, Hu Bo, Cheng Shi-Yuan

机构信息

The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Department of Pathology and Neurological Surgery, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

出版信息

Neuro Oncol. 2025 Mar 25. doi: 10.1093/neuonc/noaf086.

DOI:10.1093/neuonc/noaf086

PMID:40128633

Abstract

BACKGROUND

Isocitrate dehydrogenase mutant (IDH-mut) gliomas represent a distinct subtype of glioma, characterized by a relatively better prognosis compared to IDH wildtype (wt) glioblastoma (GBM). Despite this advantage, these tumors remain incurable due to the limited availability of effective treatments. Targeting SHP2, a non-receptor protein tyrosine phosphatase, is a promising therapeutic strategy for several types of human cancers. In this study, we aim to determine the efficacy of SHP inhibition in IDH-mut gliomas.

METHODS

Bioinformatic and biological analyses revealed increased expression and activation of the PDGFRA-SHP2-ERK pathway in clinical IDH-mut gliomas and patient-derived IDH-mut glioma stem-like cells (GSCs). The effects of SHP2 inhibition, alone or with radiation therapy (RT), were assessed through assays including cell growth, sphere formation, cell differentiation markers, flow cytometry, immunoblotting, immunohistochemistry, and orthotopic brain tumor xenografts.

RESULTS

PDGFRA expression was elevated in IDH-mut gliomas and GSCs, activating the SHP2-ERK pathway. SHP099, a SHP2 inhibitor, reduced GSC tumorigenicity in vitro and in vivo by disrupting SHP2-ERK signaling and promoting differentiation. SHP099 also enhanced cytotoxicity of RT, the standard treatment for IDH-mut glioma, in IDH-mut GSCs and orthotopic glioma models. Mechanistically, the PDGFRA-SHP2-ERK axis is activated in IDH-mut gliomas and RT further activates this pathway. Targeting SHP2 suppressed ERK signaling thereby enhancing the therapeutic effect of RT.

CONCLUSION

Combining SHP2 inhibition with RT is a promising therapeutic avenue for IDH-mut glioma by suppressing the activated SHP2-ERK axis.

摘要

背景

异柠檬酸脱氢酶突变型（IDH-mut）胶质瘤是胶质瘤的一种独特亚型，与IDH野生型（wt）胶质母细胞瘤（GBM）相比，其预后相对较好。尽管有这一优势，但由于有效治疗方法有限，这些肿瘤仍然无法治愈。靶向SHP2（一种非受体蛋白酪氨酸磷酸酶）是几种人类癌症的一种有前景的治疗策略。在本研究中，我们旨在确定抑制SHP在IDH-mut胶质瘤中的疗效。

方法

生物信息学和生物学分析显示，在临床IDH-mut胶质瘤和患者来源的IDH-mut胶质瘤干细胞样细胞（GSCs）中，血小板衍生生长因子受体α（PDGFRA）-SHP2-细胞外信号调节激酶（ERK）通路的表达和激活增加。通过细胞生长、成球、细胞分化标志物、流式细胞术、免疫印迹、免疫组化和原位脑肿瘤异种移植等试验，评估单独或联合放射治疗（RT）抑制SHP2的效果。

结果

PDGFRA在IDH-mut胶质瘤和GSCs中表达升高，激活SHP2-ERK通路。SHP2抑制剂SHP099通过破坏SHP2-ERK信号传导和促进分化，在体外和体内降低了GSC的致瘤性。SHP099还增强了RT（IDH-mut胶质瘤的标准治疗方法）对IDH-mut GSCs和原位胶质瘤模型的细胞毒性。从机制上讲，PDGFRA-SHP2-ERK轴在IDH-mut胶质瘤中被激活，RT进一步激活该通路。靶向SHP2抑制ERK信号传导，从而增强RT的治疗效果。