Integrated Proteogenomic Characterization of Glioblastoma Evolution

The evolutionary trajectory of glioblastoma is a multifaceted biological process thatextends beyond genetic alterations alone. Here, we perform an integrative proteogenomicanalysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellularstate at diagnosis and replacement by activation of neuronal transition and synaptogenicpathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that themolecular transition to neuronal state at recurrence is marked by post-translationalactivation of the WNT/PCP signaling pathway and BRAF protein kinase. Consistently,multi-omic analysis of Patient-Derived Xenograft (PDX) models mirror similar patterns ofevolutionary trajectory. Inhibition of BRAF kinase impair both neuronal transition andmigration capability of recurrent tumor cells, phenotypic hallmarks of post-therapyprogression. Combinatorial treatment of temozolomide with BRAF inhibitor, vemurafenib,significantly extend the survival of PDX models. This study provides comprehensiveinsights into the biological mechanisms of glioblastoma evolution and treatmentresistance, highlighting promising therapeutic strategies for clinical intervention.