Impact of CDK7 inhibition across a range of inhibitors in the context of heat shock
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1088165 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23989358_1.fastq.gz | Fastqsanger.gz | |||
| SRR23989358_2.fastq.gz | Fastqsanger.gz | |||
| SRR23989359_1.fastq.gz | Fastqsanger.gz | |||
| SRR23989359_2.fastq.gz | Fastqsanger.gz | |||
| SRR23989369_1.fastq.gz | Fastqsanger.gz |
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Project description:Here we evaluate the effect of CDK7 inhibition in the context of heat shock across three distinct inhibitors. Two inhibitors are Syros compounds SY-5609 and SY-5102. The final inhibitor is 3MBPP1 in a CDK7 analog sensitive cell line. We find that overall the same gene programs are impacted.
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Project description:In this study we perform precision nuclear run-on sequencing (PRO-seq) to measure the altered transcriptional response upon CDK7 inhibition or RNA-seq to elucidate the response of CDK7 inhibition on steady-state RNA. We performed a heat shock time course in PRO-seq with and without the Syros CDK7 inhibitor SY5609. Matching this data we performed three deeply sequenced RNA-seq experiments with SY5609 that include no heat shock, heat shock with recovery and long heat shock with no recovery. We additionally generated two more RNA-seq datasets in heat shock conditions with another Syros inhibitor, SY5102 and in a CDK7-analog sensitive OV90 cell line treated with 3MBPP1.
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Project description:Mouse HSF1+/+ and HSF1-/- Fibroblasts Heat Shock Time Courses Scanned on Scanner 7 (Axon 4000B) Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
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Project description:Entamoeba histolytica is a protozoan parasite which causes colitis and liver abscesses. A pilot microarray consisting of 360 unique parasite genes was constructed using identical methods to the larger array (1,971 unique genes). The four arrays in this data set were used to ascertain whether the microarrays would be useful in detecting changes in transcript abundance by exposing parasites to heat shock (42 0C for 1 hr). Approximately, 17% of the genes were regulated by at least two fold including many genes previously shown to be involved in heat shock response. This data confirmed that the genomic DNA arrays were useful in detecting changes in transcript abundance. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
2005-07-22 | GSE2978 | GEO
Project description:Entamoeba histolytica is a protozoan parasite which causes colitis and liver abscesses. A pilot microarray consisting of 360 unique parasite genes was constructed using identical methods to the larger array (1,971 unique genes). The four arrays in this data set were used to ascertain whether the microarrays would be useful in detecting changes in transcript abundance by exposing parasites to heat shock (42 0C for 1 hr). Approximately, 17% of the genes were regulated by at least two fold including many genes previously shown to be involved in heat shock response. This data confirmed that the genomic DNA arrays were useful in detecting changes in transcript abundance. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. User Defined
2005-07-22 | E-GEOD-2978 | biostudies-arrayexpress
Project description:HSP90 inhibitors (HSP90i) have not entered routinely in the clinics, primarily due to the associated resistance via heat shock response (HSR) induction and dose limiting toxicity. In this study, we employed genetic KO and knockdown (KD) models of HSP90 isoforms (α and β) for extensive multi-omics-based in vitro and in vivo characterization and identified HSP90α as the primary driver of malignancy of the two isoforms in BCR-ABL1+ leukemia cells. Notably, combinatorial ex vivo drug sensitivity screenings identified CDK7 inhibitors (CDK7i) as drugs synergizing with HSP90α inhibition.
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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.
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Project description:CDK7 has emerged as a cancer target because of its pivotal roles in cell cycle progression and transcription. Several small molecule CDK7 inhibitors (CDK7i) are now in clinical evaluation. Identifying patients most likely to respond to treatment and early detection of tumour evolution towards resistance, are necessary for optimal implementation of cancer therapies. Continuous culturing of prostate cancer cells with Samuraciclib, an ATP-competitive/non-covalent CDK7i, led to outgrowth of resistant cells. RNA-seq expression analysis was undertaken to identify changes in gene expression, revealing acquistion of a mutation, c.289G>A in the CDK7 gene, causing the p.Asp97Asn change.
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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.
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Project description:Cyclin-dependent kinase 7 (CDK7) plays a critical role in the general regulation of RNA polymerase II-mediated transcription. However, the absence of selective CDK7 inhibitors has hindered the ability to investigate the consequences of acute and prolonged inhibition of CDK7 under normal and pathological conditions. Here we present the discovery and characterization of the first covalent CDK7 inhibitor, CDK7-IN-1, that has the unprecedented ability to target a unique cysteine residue located outside of the canonical kinase domain, providing an unanticipated means of achieving selectivity for CDK7 amongst the 20 known CDKs. Cancer cell line profiling indicates that a subset of cancer cell lines, including T-cell acute lymphoblastic leukemia (T-ALL), exhibit 100-fold greater sensitivity to CDK7-IN-1 over other tumor and normal cell lines. Genome-wide expression analysis in Jurkat T-ALL indicates that CDK7-IN-1 disproportionally affects RUNX1 as well as other components of the TAL1 transcriptional network and its targets, downregulating key regulators of transcription and apoptosis critical for the T-ALL state. These oncogenes are encoded by short-lived mRNA transcripts, are associated with super-enhancers, and exhibit a strong dependency on continuous transcription for sustained expression. Therefore, pharmacological modulation of CDK7 kinase activity may define a method for the identification and treatment of tumor types exhibiting extreme dependencies on transcription for maintenance of the oncogenic state. Jurkat, MM1S, Loucy, and HeLa (WT and Dox-inducible CDK7 mutant) cells were treated with various drugs including a covalent inhibitor of CDK7 (CDK7-IN-1), a reversible inhibitor of CDK7 (CDK7-IN-1), Flavopiridol, Actinomycin D, and DMSO controls. Replicates are annotated.
2014-06-22 | E-GEOD-50624 | biostudies-arrayexpress