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Loss of function of CDK7 is Synthetically Lethal with Fatty Acid Oxidation Inhibition in Glioblastoma

ABSTRACT: Loss of function of CDK7 is Synthetically Lethal with Fatty Acid Oxidation Inhibition in Glioblastoma

PROVIDER: PRJNA956908 | ENA |

REPOSITORIES: ENA

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Loss of function of CDK7 is Synthetically Lethal with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:CDK7 has been identified as a potential drug target for glioblastoma (GBM), a highly lethal primary brain tumor. However, resistance to therapy develops quickly, which may be facilitated by drug-induced reprogramming of metabolism. By combination of a transcriptome and metabolite screening analyses followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis, we demonstrated that both genetic and pharmacological (YKL-5-124 and THZ1) CDK7 inhibition elicited substantial metabolic reprogramming. Specifically, CDK7 inhibition elicited an increase of oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO) manifested by enhanced labeling of citric acid cycle intermediates from palmitic acid. Consistently, the combination treatment of CDK7 inhibitors with blockers of FAO (etomoxir) exerted substantial synergistic growth inhibition in patient derived xenograft as well as neurosphere GBM cultures, which was mainly driven by a collapse of oxidative energy metabolism. In turn, exogenous administration of adenosine triphosphate partially rescued from the cell death induced by the combination treatment. Finally, the combined administration of YKL-5-124 and etomoxir extended overall in an orthotopic patient-derived xenograft model of GBM. In summary, these data support that simultaneous targeting of CDK7 and FAO might be a potential novel therapy against GBM.

2023-09-01 | GSE229967 | GEO

SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells

Project description:SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells

| PRJNA628515 | ENA

SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells I

Project description:SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells I

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SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells II

Project description:SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells II

| PRJNA628517 | ENA

SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells II

Project description:Oncoproteins such as the BRAFV600E kinase entrust cancer cells with malignant properties, but they also create unique vulnerabilies. Therapeutic targeting of the BRAFV600E-driven cytoplasmic signaling network has proven ineffective, since patients regularly relapse with reactivation of the targeted signaling pathways. Here, we identified the nuclear protein SFPQ to be synthetically lethal with BRAFV600E in a loss-of-function shRNA screen. SFPQ depletion decreased proliferation and induced apoptosis in BRAFV600E-driven colorectal and melanoma cells, and reduced tumor growth in xenografts. Mechanistically, SFPQ loss in BRAF-mutant cancer cells triggered the Chk1-dependent replication checkpoint, resulting in replication stress in the absence of overt DNA damage. Affected cells stalled in S-Phase with hallmark signs of impaired replication factories. Induction of BRAFV600E and concomitant loss of SFPQ sensitized cells to a combination of DNA replication checkpoint inhibitors and chemically induced replication stress, pointing towards future therapeutic approaches exploiting nuclear vulnerabilities induced by BRAFV600E.

2020-04-27 | GSE149370 | GEO

SFPQ depletion is synthetically lethal with BRAFV600E in colorectal cancer cells I

2019-12-31 | GSE116631 | GEO

Activation of the Mitochondrial ClpP protease is Synthetically Lethal with HDAC1/2 Inhibition in Glioblastoma Model Systems

Project description:Activation of the Mitochondrial ClpP protease is Synthetically Lethal with HDAC1/2 Inhibition in Glioblastoma Model Systems

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Epigenetic Targeting of Mcl-1 is Synthetically Lethal with Bcl-xL/Bcl-2 Inhibition in Model Systems of Glioblastoma

Project description:Epigenetic Targeting of Mcl-1 is Synthetically Lethal with Bcl-xL/Bcl-2 Inhibition in Model Systems of Glioblastoma

| PRJNA634319 | ENA

Primary murine embryonic fibroblasts (MEFs): Cdk7 wild type versus Cdk7 KO

Project description:Transcriptional profiling of primary Cdk7lox/lox MEFs comparing Adeno-Cre vs Adeno-GFP infected controls. Samples were obtained 7 days after the Adeno-Cre mediated elimination of Cdk7. Goal was to determine the effects of Cdk7 elimination on RNA polII-mediated transcription. Two-condition experiment, Adeno-Cre vs. Adeno-GFP infected Cdk7lox/lox MEFs. Biological replicates: 10 independent primary MEF preparations.

2012-04-17 | E-GEOD-36050 | biostudies-arrayexpress

Obesity and fatty acid oxidation

Project description:It has been found that fat oxidation is reduced in the skeletal muscle of obese humans. This study aims to identify the mRNA of proteins involved in fat oxidation that may be reduced in obese and morbidly obese individuals. Information gathered will help in understanding how obesity contributes to cardiovascular disease via insulin resistance. Keywords: other

2003-07-16 | GSE474 | GEO

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