PTEN DEFICIENCY LEADS TO PROTEASOME ADDICTION, A NOVEL VULNERABILITY IN GLIOBLASTOMA

We found that GSCs were highly sensitive to proteasome inhibition due to an underlying dependency on an increased protein synthesis rate, and loss of autophagy, associated with PTEN loss and activation of the PI3K/mTOR pathway. In contrast, combinatory inhibition of autophagy and the proteasome, resulted in enhanced cytotoxicity specifically in GSCs that did express PTEN. Finally, proteasome inhibition specifically increased cell death markers in 3D glioblastoma organoids, suppressed tumor growth, and increased survival of mice orthotopically engrafted with GSCs. As perturbations of the PI3K/mTOR pathway occur in nearly 50% of GBMs, these findings suggest that a significant fraction of these tumors could be vulnerable to proteasome inhibition. High throughput drug screening was performed on 5 GSCs followed by a dose response assay of the 5 identified original “hits” in 15 samples. A PI3K/mTOR dependency to a proteasome inhibitor (carfilzomib), was confirmed by genetic and pharmacologic experiments. Proteasome inhibition response signatures were derived from proteomic and bioinformatic analysis. Molecular mechanism of action was determined using 3-dimensional (3D) GBM organoid models and preclinical orthotopic GBM models