Systematic name M40000
Brief description 102 proteins were identified that were specifically and significantly accumulated after proteasome inhibition with carfilzomibin the PTEN-KO GBM spheres compared with placebo-treated and were not statistically present in the PTEN-WT drug vs placebo group at the proteomic level, this proteomic signature was then coorelated with the RNA-level transcriptomic response to carfilzomib using GSEA. The leading edge of the enrichment result was selected as the response signature.
Full description or abstract Background
Glioblastoma (GBM) is the most common primary brain tumor in adults with a median survival of approximately 15 months, therefore, more effective treatment options for GBM are required. To identify new drugs targeting glioblastomas, we performed a high throughput drug screen using patient-derived neurospheres cultured to preferentially retain their glioblastoma stem cell (GSC) phenotype.
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 in3D 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.
Proteasome inhibition is a potential synthetic lethal therapeutic strategy for GBM with proteasome addiction due to a high protein synthesis rate and autophagy deficiency
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 33428749   Authors: Benitez JA,Finlay D,Castanza A,Parisian AD,Ma J,Longobardi C,Campos A,Vadla R,Izurieta A,Scerra G,Koga T,Long T,Chavez L,Mesirov JP,Vuori K,Furnari F
Exact source noab001_suppl_Supplementary_Table_S3 PIRLE, CORE ENRICHMENT = YES
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