Abstract 6946: Targeting PDGFRa-SHP2 signaling enhances radiotherapy in IDH1 mutant glioma

Abstract Background: Isocitrate dehydrogenase mutant (IDH-mut) gliomas represent a distinct subtype of glioma with a somewhat better prognosis. However, despite this, they remain incurable due to the limited availability of effective treatments. Targeting SHP2, a non-receptor protein tyrosine phosphatase, shows promise as a therapeutic strategy for cancers, including IDH wildtype (WT) glioblastoma (GBM). However, it is unknown whether IDH-mutant gliomas respond to SHP2 inhibition. Methods: Bioinformatic and biological analyses revealed increased expression and activation of the PDGFRα-SHP2-ERK pathway in IDH-mutant 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, flow cytometry, immunoblotting, orthotopic brain tumor xenografts, and immunohistochemistry. Results: PDGFRα 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, on IDH-mut GSCs and orthotopic glioma models. Mechanistically, the PDGFRα-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 shows promising therapeutic efficacy for IDH-mut glioma by suppressing the activated SHP2-ERK axis. Citation Format: Xiaozhou Yu, Xiao Song, Deanna Tiek, Runxin Wu, Maya Walker, Craig Horbinski, Bo Hu, Shi-Yuan Cheng. Targeting PDGFRa-SHP2 signaling enhances radiotherapy in IDH1 mutant glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6946.