Targeting the PDGFRa-SHP2 Signaling Enhances Therapeutic Effect of Radiotherapy on Treating IDH1 Mutant Glioma

Background: Isocitrate dehydrogenase mutant (IDH-mut) glioma represents a distinct subtype of adult glioma. Although IDH-mut glioma displays slightly better prognosis among adult gliomas, these tumors are still incurable largely due to the lack of effective treatments. Targeting SHP2 has been shown to be a promising therapeutic approach in various types of malignancies, and our previous research demonstrated its efficacy against IDH wildtype (WT) glioblastoma (GBM). However, whether IDH-mutant gliomas are responsive to SHP2 inhibition remains unknown. Methods: Bioinformatic and biological analyses revealed increased expression and activation of PDGFRα-SHP2-ERK pathway in clinical IDH-mutant gliomas and patient-derived IDH-mut glioma stem-like cells (GSCs). Therapeutic effects of a SHP2 inhibitor on inhibition of the PDGFRα-SHP2-ERK signaling and tumorigenicity of IDH-mut GSCs, individually or in combination with radiation therapy (RT) were assessed by cell growth, glioma sphere formation, cell differentiation, flow cytometry, immunoblotting, orthotopic brain tumor xenograft, bioluminescent tracking, and immunohistochemistry. Results: We found a marked increase in PDGFRα expression in clinical IDH-mutant gliomas and IDH-mut GSCs, leading to the activation of the downstream SHP2-ERK pathway. Treatment with a blood-brain barrier-penetrable SHP2 inhibitor, SHP099 significantly inhibited GSC tumorigenic properties in vitro and in vivo by impeding SHP2-ERK axis and inducing cellular differentiation. Additionally, SHP099 treatment synergistically enhanced cytotoxicity of RT on IDH-mut GSCs in vitro and in orthotopic glioma xenografts, the standard treatment for IDH-mut glioma. Mechanistically, the PDGFRα -SHP2-ERK axis is activated in IDH-mut gliomas while radiation activates the SHP2-ERK pathway. Targeting SHP2 suppressed the activated ERK signaling thereby enhancing cytotoxicity of RT against IDH-mut gliomas. Conclusion: Targeting SHP2 in combination with RT for treating IDH-mut glioma displays promising therapeutic efficacy through suppressing a preferentially activated SHP2-ERK axis in IDH-mut gliomas.