Dynamic multi-OMICs of glioblastoma reveal sensitivity to neddylation inhibition dependent on nuclear PTEN and DNA replication pathways: Nuclear PTEN mediates MLN4924 sensitivity in GBM

Abstract

AbstractFinding 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 intactPTENdie due to DNA damage and re-replication events. Loss ofPTENdrives 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 thatPTENstatus serves as both a novel biomarker for MLN4924 response in GBM and reveals a vulnerability to TOP2A inhibitors in combination with MLN4924.SummaryNeddylation inhibition kills glioma cells by DNA damage and re-replication events which are dependent on wild-type nuclear PTEN.