PXD022934

PXD022934 is an original dataset announced via ProteomeXchange.

Title	PTEN DEFICIENCY LEADS TO PROTEASOME ADDICTION, A NOVEL VULNERABILITY IN GLIOBLASTOMA
Description	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. High throughput drug screening was performed on GSCs followed by a second dose response assay of the 5 identified original hits. A PI3K/mTOR dependency to a proteasome inhibitor (carfilzomib), was confirmed by gain of function and loss of function experiments. Proteasome inhibition response signatures were derived from proteomic and bioinformatic analysis. Molecular mechanism of action was determined using in vitro 3-dimensional (3D) GBM organoid models and in vivo preclinical orthotopic GBM models. 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 PTEN/ PI3K axis occur in nearly 50% of GBMs, these findings suggest that a significant fraction of these tumors could be vulnerable to proteasome inhibition.
HostingRepository	MassIVE
AnnounceDate	2021-01-24
AnnouncementXML	Submission_2021-01-24_19:55:11.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alexandre Rosa Campos
SpeciesList	scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationList	Oxidation
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-04 13:32:54	ID requested
⏵ 1	2021-01-24 19:55:12	announced

no publication

submitter keyword: Glioblastoma, proteasome, PTEN, organoids, neurospheres

Frank Furnari
contact affiliation	University of California San Diego
contact email	ffurnari@ucsd.edu
lab head
Alexandre Rosa Campos
contact affiliation	SBP Medical Discovery Institute
contact email	arosacampos@sbpdiscovery.org
dataset submitter

MassIVE dataset URI

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