Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA305433 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:CDK7 Inhibition Suppresses Melanoma Growth By Depleting A Super-enhancer Associated "Achilles" Lineage Cluster
| PRJNA305434 | ENA
Project description:CDK7 Inhibition Suppresses Melanoma Growth By Depleting A Super-enhancer Associated Achilles Lineage Cluster [Array]
| PRJNA305414 | ENA
Project description:Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not ER/PR+ breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of TNBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be useful therapy for this challenging cancer. Expression microarrays in H3K27ac in triple-negative breast cancer +/- treatment with covalent CDK7 inhibitor THZ1 treatment
2015-09-24 | E-GEOD-69106 | biostudies-arrayexpress
Project description:Basal-like breast cancer (BBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that BBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that basal but not luminal breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. BBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of BBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in BBC and CDK7 inhibition may be useful therapy for this challenging cancer. ChIP-Seq for H3K27ac in basal-like breast cancer and luminal-like breast cancer cell lines
2015-01-23 | E-GEOD-65201 | biostudies-arrayexpress
Project description:Cutaneous malignant melanoma (CMM) lacks targeted therapies beyond the oft-circumvented BRAF inhibitors. Part of the difficulty in treating melanomas has been attributed to a strong survival program controlled by melanocyte transcription factors such as MITF - a phenomenon first described in melanoma as “lineage dependency.” Recently, a highly selective covalent CDK7 inhibitor (THZ1) has been shown to potently suppress the growth of various cancers through the depletion of master transcription-regulating oncogenes and the disruption of their attendant super-enhancers. We now show that melanoma cells are highly sensitive to CDK7 inhibition and that a melanocyte “lineage cluster,” whose members are transcriptionally driven by super-enhancers, is also strongly suppressed by THZ1. These results point to CDK7 inhibition as a viable strategy to deprive oncogenic transcription and suppress tumor growth in melanoma.
2017-10-23 | GSE75810 | GEO
Project description:Cutaneous malignant melanoma (CMM) lacks targeted therapies beyond the oft-circumvented BRAF inhibitors. Part of the difficulty in treating melanomas has been attributed to a strong survival program controlled by melanocyte transcription factors such as MITF - a phenomenon first described in melanoma as “lineage dependency.” Recently, a highly selective covalent CDK7 inhibitor (THZ1) has been shown to potently suppress the growth of various cancers through the depletion of master transcription-regulating oncogenes and the disruption of their attendant super-enhancers. We now show that melanoma cells are highly sensitive to CDK7 inhibition and that a melanocyte “lineage cluster,” whose members are transcriptionally driven by super-enhancers, is also strongly suppressed by THZ1. These results point to CDK7 inhibition as a viable strategy to deprive oncogenic transcription and suppress tumor growth in melanoma.
2017-10-23 | GSE75814 | GEO
Project description:Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not ER/PR+ breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of TNBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be useful therapy for this challenging cancer.
2015-09-24 | GSE69106 | GEO
Project description:Basal-like breast cancer (BBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that BBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that basal but not luminal breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. BBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of BBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in BBC and CDK7 inhibition may be useful therapy for this challenging cancer.
2015-01-23 | GSE65201 | GEO
Project description:Transcriptional co-acticvators inhibition is proving to be a powerful mean against cancer cells that shown a novel hallmarks named transcriptional addiction. This dependecy on co-activars activity lays on their presence in clusters of enhancer regulatory regions called Super-enhancers (SEs) that establish high level of expression of genes important for cancer phisiology such as oncogenes and master transcription factors of the cellular lineage of origin. Among these co-activators in SEs is the kinase CDK7 of the basal transcription factor TFIIH. Here, using a large panel of melanoma cell lines, we observed an overall dependency of melanoma cells in CDK7 activity by inhibiting its function through the drug THZ1. However, by chronically exposing melanoma cells to THZ1, they univocally become resistant, switching phenotype toward a mesenchymal-like state.
2020-09-18 | GSE158119 | GEO
Project description:Transcriptional co-acticvators inhibition is proving to be a powerful mean against cancer cells that shown a novel hallmarks named transcriptional addiction. This dependecy on co-activars activity lays on their presence in clusters of enhancer regulatory regions called Super-enhancers (SEs) that establish high level of expression of genes important for cancer phisiology such as oncogenes and master transcription factors of the cellular lineage of origin. Among these co-activators in SEs is the kinase CDK7 of the basal transcription factor TFIIH. Here, using a large panel of melanoma cell lines, we observed an overall dependency of melanoma cells in CDK7 activity by inhibiting its function through the drug THZ1. However, by chronically exposing melanoma cells to THZ1, they univocally become resistant, switching phenotype toward a mesenchymal-like state. By comparing the transcriptome of artificial resistant and untreated cells in culture, we observed upregulation of the transcription factor GATA6 which control indeed a small regulon that includes genes involved in multi-drug resistance (MDR).
2021-01-09 | GSE164431 | GEO