Temporally evolving neuronal remodeling via the CTNNB1–NRG3–ERBB4 axis drives therapy resistance in glioblastoma

Glioblastoma (GBM) remains highly lethal despite early therapeutic responses, as resistance inevitably emerges. While clinical studies show improvements in progression-free survival (PFS) during the early response (ER) phase, the molecular trajectory bridging ER and recurrent resistance (RR)—and the adaptive resistance programs temporally engaged during this transition— remain poorly understood. To dissect the dynamic molecular evolution underlying therapy resistance, patient-derived xenograft (PDX) models were treated with anti-VEGF therapy. Longitudinal proteogenomic profiling across multiple time points was performed to capture time-resolved molecular changes associated with the tumor response to the therapy. Longitudinal analyses revealed a dynamic, temporally evolving response trajectory, with an initial response phase (IRP) marked by neuronal-like remodeling, and a late response phase (LRP) characterized by mesenchymal transdifferentiation and metabolic adaptation. Proteomic and phosphoproteomic analyses identified the CTNNB1–NRG3–ERBB4 signaling axis as a key driver of neuronal-like remodeling during the IRP. Mechanistically, β-catenin activation upregulated NRG3, promoting postsynaptic scaffold remodeling, while pharmacological inhibition of β-catenin/CBP with PRI-724 disrupted this neuronal program and significantly extended survival in vivo. These findings place neuronal-like remodeling within a time-resolved framework of tumor adaptation to anti-VEGF therapy in GBM and highlight the CTNNB1–NRG3–ERBB4 axis as a tractable therapeutic target, providing a rationale for combination strategies to overcome anti-VEGF therapy failure.