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

Abstract

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.