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

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

PROVIDER: PRJNA688156 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13311680_1.fastq.gz	Fastqsanger.gz
	SRR13311680_2.fastq.gz	Fastqsanger.gz
	SRR13311681_1.fastq.gz	Fastqsanger.gz
	SRR13311681_2.fastq.gz	Fastqsanger.gz
	SRR13311682_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

2020-12-29 | GSE163906 | GEO

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

Project 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.

2020-12-04 | MSV000086560 | MassIVE

PTEN deficiency leads to proteasome addiction: a novel vulnerability in glioblastoma.

Project description:BackgroundGlioblastoma (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 GBMs, we performed a high-throughput drug screen using patient-derived neurospheres cultured to preferentially retain their glioblastoma stem cell (GSC) phenotype.MethodsHigh-throughput drug screening was performed on GSCs followed by a dose-response assay of the 5 identified original "hits." 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 three-dimensional (3D) GBM-organoids and preclinical orthotopic models.ResultsWe 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 GBM-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.ConclusionsProteasome inhibition is a potential synthetic lethal therapeutic strategy for GBM with proteasome addiction due to a high protein synthesis rate and autophagy deficiency.

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Expression data from cholangiocarcinoma cell lines with PTEN overexpression

Project description:To explore the mechanism of PTEN function, we determined the gene expression profiles of RBE and HCCC-9810 cells infected with PTEN adenovirus. Pathway and GO-term enrichment analyses suggested that the proteasome and ubiquitin-mediated proteolysis pathways were specifically affected in HCCC-9810 cells

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PTEN deficiency exposes a requirement for an ARF GTPase module in integrin-dependent invasion in ovarian cancer

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