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

IF 16.4 1区医学 Q1 CLINICAL NEUROLOGY

Neuro-oncology Pub Date : 2025-03-25 DOI:10.1093/neuonc/noaf086

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

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引用次数: 0

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.

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靶向pdgfr - shp2信号增强idh1突变胶质瘤的放疗

背景：异柠檬酸脱氢酶突变（IDH-mut）胶质瘤是一种独特的胶质瘤亚型，与IDH野生型（wt）胶质母细胞瘤（GBM）相比，其预后相对较好。尽管有这样的优势，但由于有效的治疗方法有限，这些肿瘤仍然无法治愈。针对SHP2（一种非受体蛋白酪氨酸磷酸酶）是一种很有前景的治疗几种人类癌症的策略。在本研究中，我们旨在确定SHP抑制IDH-mut胶质瘤的疗效。方法：生物信息学和生物学分析显示，pdgfr - shp2 - erk通路在临床IDH-mut胶质瘤和患者来源的IDH-mut胶质瘤干细胞（GSCs）中表达和激活增加。通过细胞生长、球体形成、细胞分化标志物、流式细胞术、免疫印迹、免疫组织化学和原位脑肿瘤异种移植等检测来评估单独或放射治疗（RT）对SHP2抑制的影响。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的细胞毒性，RT是IDH-mut胶质瘤的标准治疗方法，在IDH-mut GSCs和原位胶质瘤模型中。在机制上，pdgfr - shp2 - erk轴在IDH-mut胶质瘤中被激活，RT进一步激活了这一途径。结论：通过抑制活化的SHP2-ERK轴，将SHP2抑制与RT联合治疗IDH-mut胶质瘤是一条很有前景的治疗途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuro-oncology 医学-临床神经学

CiteScore

27.20

自引率

6.30%

发文量

1434

审稿时长

3-8 weeks

期刊介绍： Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.