Prickle4 Drives Microenvironmental Remodeling and Resistance to Parp Inhibition in IDH‐Mutant Glioma

IDH‐mutant gliomas exhibit sensitivity to PARP inhibitors (PARPi) owing to oncometabolite 2‐HG‐induced DNA repair defects. PARPi treatment induces resistance by upregulating Prickle4, which promotes VEGF‐driven angiogenesis. Combining PARPi veliparib with anti‐angiogenic lenvatinib blocks this pathway, causing tumor regression and prolonged survival in models, revealing a new adaptive resistance mechanism and supporting a promising combination strategy. Abstract Mutations in isocitrate dehydrogenase (IDH) genes sensitize gliomas to PARP inhibition (PARPi) by inducing epigenetic reprogramming of DNA damage repair circuits. However, tumors treated with PARPi eventually relapse despite initial responsiveness. In this study, it is demonstrated that the anti‐angiogenic agent lenvatinib synergizes effectively with PARPi, resulting in substantial tumor regression and significantly extended survival. Genomic analysis of tumors reveals that PARPi induces widespread transcriptomic changes that are predominantly pro‐inflammatory, thereby promoting tumor angiogenesis. Prickle4, a planar cell polarity protein, is identified as a critical mediator of PARPi‐induced neovascularization. Targeting Prickle4 effectively overcomes PARPi resistance in these tumors. Collectively, these findings identified the Prickle4‐mediated microenvironmental remodeling as the key resistance mechanism to PARPi, and support the therapeutic promise of multimodal therapy combining PARPi with anti‐angiogenic agents for glioma treatment. IDH-mutant gliomas exhibit sensitivity to PARP inhibitors (PARPi) owing to oncometabolite 2-HG-induced DNA repair defects. PARPi treatment induces resistance by upregulating Prickle4, which promotes VEGF-driven angiogenesis. Combining PARPi veliparib with anti-angiogenic lenvatinib blocks this pathway, causing tumor regression and prolonged survival in models, revealing a new adaptive resistance mechanism and supporting a promising combination strategy. Abstract Mutations in isocitrate dehydrogenase (IDH) genes sensitize gliomas to PARP inhibition (PARPi) by inducing epigenetic reprogramming of DNA damage repair circuits. However, tumors treated with PARPi eventually relapse despite initial responsiveness. In this study, it is demonstrated that the anti-angiogenic agent lenvatinib synergizes effectively with PARPi, resulting in substantial tumor regression and significantly extended survival. Genomic analysis of tumors reveals that PARPi induces widespread transcriptomic changes that are predominantly pro-inflammatory, thereby promoting tumor angiogenesis. Prickle4, a planar cell polarity protein, is identified as a critical mediator of PARPi-induced neovascularization. Targeting Prickle4 effectively overcomes PARPi resistance in these tumors. Collectively, these findings identified the Prickle4-mediated microenvironmental remodeling as the key resistance mechanism to PARPi, and support the therapeutic promise of multimodal therapy combining PARPi with anti-angiogenic agents for glioma treatment. Advanced Science, EarlyView.