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Single-cell transcriptomic profiling of mouse lung tumor in response to CDK7 inhibitor, anti-PD-1 and combination treatment (Experiment 1)

ABSTRACT: We performed single-cell RNA sequencing (scRNAseq) analysis on the mouse lung tissues from small cell lung tumor-bearing mice treated with CDK7 inhibitor YKL, anti-PD-1 and combination treatment

ORGANISM(S): Mus musculus

PROVIDER: GSE129297 | GEO | 2019/12/27

REPOSITORIES: GEO

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Single-cell transcriptomic profiling of mouse lung tumor in response to CDK7 inhibitor, anti-PD-1 and combination treatment (Experiment 2)

Project description:We performed single-cell RNA sequencing (scRNAseq) analysis on the mouse lung tissues from small cell lung tumor-bearing mice treated with CDK7 inhibitor YKL, anti-PD-1 and combination treatment

2019-12-27 | GSE129298 | GEO

Transcriptomic profiling of mouse lung tumor cells in response to CDK7 inhibitor treatment

Project description:We performed RNA sequencing analysis on the mouse lung tumor cells treated with CDK7 inhibitor YKL in vitro

2019-12-27 | GSE137636 | GEO

Single-cell transcriptomic profiling of mouse KrasG12DP53-/- (KP) lung tumors in response to tumor cell intrinsic Asf1a knockout (KO), anti-PD-1 or combination treatment (Asf1a KO + anti-PD-1).

Project description:We performed single-cell RNA sequencing (scRNAseq) analysis on the mouse lung tissues from KP tumor-bearing mice treated with tumor cell intrinsic Asf1a KO, anti-PD-1 or combination treatment

2019-11-26 | GSE133604 | GEO

CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma

Project description:Therapeutic targeting of CDK7 has proven beneficial in pre-clinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in multiple myeloma (MM) patient cells; and its selective targeting counteracts E2F activity via perturbation of the CDKs/Rb axis and impairs MYC-regulated metabolic gene signatures translating into defects in glycolysis and reduced levels of lactate production in MM cells. CDK7 inhibition using the covalent small molecule inhibitor YKL-5-124 elicits a strong therapeutic response with minimal effects on normal cells, and causes in vivo tumor regression increasing survival in several MM mouse models including a genetically engineered mouse model of MYC-dependent MM. Through its role as a critical cofactor and regulator of MYC and E2F activity, CDK7 is therefore a master regulator of oncogenic cellular programs supporting MM growth and survival, and a valuable therapeutic target providing rationale for development of YKL-5-124 for clinical use.

2023-02-01 | GSE172441 | GEO

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

Activation of the p53 transcriptional program sensitizes cancer cells to Cdk7 inhibitors

Project description:Cdk7, the CDK-activating kinase and transcription factor IIH component, is a target of inhibitors that kill cancer cells by exploiting tumor-specific transcriptional dependencies. However, whereas selective inhibition of analog-sensitive (AS) Cdk7 in colon cancer derived cells arrests division and disrupts transcription, it does not by itself trigger apoptosis efficiently. Here we show that p53 activation by 5-fluorouracil or nutlin-3 synergizes with a reversible Cdk7as inhibitor to induce cell death. Synthetic lethality was recapitulated with covalent inhibitors of wild-type Cdk7, THZ1 or the more selective YKL-1-116. The effects were allele-specific; a CDK7as mutation conferred both sensitivity to bulky adenine analogs and resistance to covalent inhibitors. Non-transformed colon epithelial cells were resistant to these combinations, as were cancer-derived cells with p53-inactivating mutations. Apoptosis was dependent on death receptor DR5, a p53 transcriptional target whose expression was refractory to Cdk7 inhibition. Therefore, p53 activation induces transcriptional dependency to sensitize cancer cells to Cdk7 inhibition.

2017-10-10 | GSE99794 | GEO

Single-cell transcriptomic profiling of mouse lung tumor in response to CDK7 inhibitor, anti-PD-1 and combination treatment (Experiment 2)

Project description:Single-cell transcriptomic profiling of mouse lung tumor in response to CDK7 inhibitor, anti-PD-1 and combination treatment (Experiment 2)

| PRJNA530769 | ENA

Single-cell transcriptomic profiling of mouse lung tumor in response to CDK7 inhibitor, anti-PD-1 and combination treatment (Experiment 1)

Project description:Single-cell transcriptomic profiling of mouse lung tumor in response to CDK7 inhibitor, anti-PD-1 and combination treatment (Experiment 1)

| PRJNA530768 | ENA

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Sensitive_MM_Cell_Lines_RNA-seq]

Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Sensitive MM cell lines (H929 and MM1S; 24 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi

2022-04-01 | GSE172444 | GEO

CDK7 inhibition interdicts deregulated transcription and cell cycle control in multiple myeloma [Resistant_MM_Cell_Lines_24Hr_RNA-seq]

Project description:Cyclin dependent kinases (CDKs) are high value therapeutical targets owing to their important roles in regulating transcription and the cell cycle — two pathways commonly altered in cancer and especially in multiple myeloma (MM). Among CDKs, CDK7 uniquely bridges cell cycle and transcriptional control by activating other cell cycle CDKs and forming the general transcription factor TFIIH. Utilizing a recently developed highly selective covalent inhibitor of CDK7, we demonstrate that CDK7 inhibition elicits a strong therapeutic response in MM blocking proliferation in vitro and driving tumor regression and prolonged survival in vivo. CDK7 inhibition counteracts molecular hallmarks of deregulated cell cycle control at the G1/S checkpoint. Additionally, we show CDK7 inhibition selectively downregulates oncogenic E2F and cell cycle gene expression programs. Combination treatment with JQ1 which target oncogenic enhancer driven gene expression programs proved highly synergistic. These results support CDK7 as an attractive and therapeutically actionable molecular vulnerability in MM. Cell count normalized RNA-seq in Resistant MM cell lines (XG1 and AMO1; 18 total samples; 3 technical replicates) upon treatment with the selective covalent CDK7 inhibitor YKL-5-124 Mariateresa,Fulciniti Nikhil,Munshi

2022-04-01 | GSE172443 | GEO

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