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Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor (Affymetrix)

ABSTRACT: Small cell lung cancer (SCLC) is an aggressive disease with high mortality. The identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library we observe that SCLC is sensitive to transcription-targeting drugs, and in particular to THZ1, a newly identified covalent inhibitor of cyclin-dependent kinase 7 (CDK7). We find that expression of super-enhancer associated transcription factor genes including MYC family proto-oncogenes and neuroendocrine lineage-specific factors are highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a novel treatment paradigm for targeted SCLC therapy. Microarray expression in small cell lung cancer lines treated with DMSO or THZ1

ORGANISM(S): Homo sapiens

SUBMITTER: Young Richard

PROVIDER: S-ECPF-GEOD-62609 | biostudies-other |

REPOSITORIES: biostudies-other

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Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor.

Project description:Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy.

| S-EPMC4261156 | biostudies-literature

Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor (Affymetrix)

Project description:Small cell lung cancer (SCLC) is an aggressive disease with high mortality. The identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library we observe that SCLC is sensitive to transcription-targeting drugs, and in particular to THZ1, a newly identified covalent inhibitor of cyclin-dependent kinase 7 (CDK7). We find that expression of super-enhancer associated transcription factor genes including MYC family proto-oncogenes and neuroendocrine lineage-specific factors are highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a novel treatment paradigm for targeted SCLC therapy. Microarray expression in small cell lung cancer lines treated with DMSO or THZ1

2014-10-23 | E-GEOD-62609 | biostudies-arrayexpress

Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor (Affymetrix)

2014-10-23 | GSE62609 | GEO

Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-10-23 | E-GEOD-62614 | biostudies-arrayexpress

Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor

Project description:This SuperSeries is composed of the SubSeries listed below.

2014-10-23 | GSE62614 | GEO

Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor (ChIP-seq)

Project description:Small cell lung cancer (SCLC) is an aggressive disease with high mortality. The identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library we observe that SCLC is sensitive to transcription-targeting drugs, and in particular to THZ1, a newly identified covalent inhibitor of cyclin-dependent kinase 7 (CDK7). We find that expression of super-enhancer associated transcription factor genes including MYC family proto-oncogenes and neuroendocrine lineage-specific factors are highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a novel treatment paradigm for targeted SCLC therapy. ChIP-Seq for H3K27ac in small cell lung cancer lines

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Targeting transcriptional dependencies in cancer using a covalent CDK7 inhibitor

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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Targeting transcriptional dependencies in cancer using a covalent CDK7 inhibitor (expression)

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

Targeting transcriptional dependencies in cancer using a covalent CDK7 inhibitor

Project description:This SuperSeries is composed of the SubSeries listed below.

2013-12-23 | GSE50625 | GEO