Dynamic multi-OMICs of glioblastoma reveal sensitivity to neddylation inhibition dependent on nuclear PTEN and DNA replication pathways

Finding and matching drugs to treat subsets of cancers remains a daunting challenge of precision medicine. Neddylation inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer including glioblastoma (GBM). We report vulnerability to neddylation inhibition by MLN4924 in a subset of GBM preclinical models and identify mechanisms underlying this differential response. MLN4924 treatment of GBM cells with intact PTEN die due to DNA damage and re-replication events. Loss of PTEN drives resistance to MLN4924. Time-course transcriptomics elevates PTEN signaling, DNA replication, and chromatin instability pathways as significant differentiators between MLN4924-sensitive and resistant models. Shotgun proteomics corroborates these findings and also identifies elevated TOP2A in resistant models. TOP2A inhibitors combined with MLN4924 prove synergistic. We show that PTEN status serves as both a novel biomarker for MLN4924 response in GBM and reveals a vulnerability to TOP2A inhibitors in combination with MLN4924.