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CDK7 Inhibition Suppresses Melanoma Growth By Depleting A Super-enhancer Associated Achilles Lineage Cluster [Array]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE75810 | GEO | 2017/10/23

SECONDARY ACCESSION(S): PRJNA305414

REPOSITORIES: GEO

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CDK7 Inhibition Suppresses Melanoma Growth By Depleting A Super-enhancer Associated "Achilles" Lineage Cluster [ChIP-Seq]

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

Genome-wide maps of chromatin state in primary MLL-AF9 AML

Project description:Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly-gained SEs in primary mouse AML cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis.

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Project description:CDK7 is a cycline-dependent kinase part of the basal transcription factor TFIIH involved in the formation of the pre-inithiation complex of RNApol II dependent-genes. Despite it's well known genomic localization at the level of gene's promoter, it has been recently observed from Kwiatkowski et al., (2014) that CDK7 can be found also in large clusters of gene regulatory elements called Super-enhancers (SEs) of both normal and cancer cells. Here we report that CDK7 is resembling such distribution in a human melanoma context, in particular at the level of genes important in melanoma physiology such as the master transcription factors MITF and SOX10 which indeed, following the inhibition of CDK7 with the molecule THZ1, are rapidly downregulated at very low nanomolar concentration.

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CDK7 inhibition suppresses Castration-Resistant Prostate Cancer through MED1 inactivation

Project description:We performed RNA-seq and ChIP-seq in three prostate cell lines (VCaP, LNCaP and DU145) to ascertain the role of the mediator complex MED1 in AR signaling. Upon androgen stimulation, MED1 undergoes phosphorylation by CDK7 and physically engages with AR at super-enhancer sites, which is essential for AR-mediated transcription. The CDK7 specific inhibitor THZ1 blunts AR-dependent neoplastic growth by preventing the co-recruitment of AR/MED1 in a genome-wide fashion, and reverts the enzalutamide resistance characterized by hyper-phosphorylated MED1. The effect of THZ1 phenocopies that for MED1 and CDK7 knockdown.

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CDK7-dependent Transcriptional Addiction in Triple-Negative Breast Cancer (Microarray)

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