Synthetic Lethality Through GSK3 Inhibition in Glioma Stem Cells via the WNT-WWC1-YAP Axis

Glioblastoma (GBM) is an aggressive brain tumor driven by glioma stem cells (GSCs), which contribute to tumor growth and therapeutic resistance. This study investigates the effects of GSK3 inhibition on GSC viability, focusing on the role of the canonical WNT signaling pathway. We found that GSK3 inhibition activates the WNT pathway, leading to upregulation of Wwc1, which downregulates Yap via LATS1 phosphorylation. This reduces GSC proliferation, self-renewal, and enhances chemosensitivity. Analysis of clinical datasets revealed that WNT pathway activation correlates with improved prognosis in proneural gliomas, particularly in IDH1-mutated tumors. Our findings suggest that targeting the WNT-Wwc1-YAP axis, particularly through GSK3 inhibition, could induce synthetic lethality in GSCs and provide a promising therapeutic strategy for gliomas. These results highlight the potential of exploiting WNT-induced synthetic lethality as a novel approach for glioma treatment.