Proteogenomic Insights Into Glioblastoma Evolution: Neuronal Reprogramming and Therapeutic Vulnerabilities

Glioblastoma (GBM) remains one of the most lethal and treatment-resistant malignancies, characterized by high recurrence rates following standard-of-care therapy. While previous longitudinal studies employing whole-exome and RNA sequencing have revealed patient-specific clonal evolution, they have not identified conserved biological programs that drive recurrence or therapeutic resistance. A recent study published in Cancer Cell presents the first integrated proteogenomic analysis of matched primary and recurrent GBMs. This integrative approach reveals a striking phenotypic transition in recurrent tumors, characterized by neuronal reprogramming supported by coordinated transcriptional, proteomic, and phosphoproteomic evidence. In this review, we contextualize these findings within the broader landscape of GBM evolution, emphasizing the mechanistic contributions of WNT/planar cell polarity (PCP) signaling and BRAF kinase activation in facilitating a neuronal-like state that enhances tumor plasticity, invasion, and treatment resistance. We further discuss how these profound insights align with preclinical models of tumor-neuron synaptic crosstalk, and propose that proteogenomics offers a powerful lens through which to uncover clinically actionable vulnerabilities. By redefining the functional landscape of recurrent GBM, the current study establishes a new framework for biomarker discovery and the rational design of targeted therapies informed by tumor evolution and neuronal niche adaptation.