Transcriptional Antagonism by CDK8 Inhibition Improves Therapeutic Efficacy of MEK Inhibitors
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ABSTRACT:
PROVIDER: PRJNA786216 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17130617_1.fastq.gz | Fastqsanger.gz | |||
| SRR17130617_2.fastq.gz | Fastqsanger.gz | |||
| SRR17130618_1.fastq.gz | Fastqsanger.gz | |||
| SRR17130618_2.fastq.gz | Fastqsanger.gz | |||
| SRR17130619_1.fastq.gz | Fastqsanger.gz |
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Project description:Aberrant RAS/MAPK signaling, a common driver of oncogenesis, can be therapeutically targeted with clinically approved MEK inhibitors. Single agent therapy ultimately results in tumor outgrowth in most settings and combination therapies are required to achieve significant clinical benefit in most advanced cancers. Here we focus on identifying MEK inhibitor-based combination therapies in RAS-mutant neuroblastoma. Mutations that activate the RAS/MAPK signaling pathway, while rare at diagnosis, are more frequent in relapsed neuroblastoma. More than 50% of children with high-risk neuroblastoma ultimately relapse and treatment options for relapsed neuroblastoma are limited so most children with relapsed disease do not survive. Here we use a genome-scale CRISPR-Cas9 functional genomic screen to identify genes that, when lost, sensitize RAS-mutant neuroblastoma to MEK inhibition. We discover that loss of either CCNC or CDK8, two members of the mediator kinase module, sensitizes neuroblastoma to MEK inhibition. Furthermore, we demonstrate that small molecule kinase inhibitors of CDK8 improve response to MEK inhibitors in vitro and in vivo in RAS-mutant neuroblastoma and other adult solid tumors, suggesting that the addition of CDK8 inhibitors could improve clinical outcome. Using transcriptional profiling, we unexpectedly find that loss of CDK8 or CCNC antagonizes the transcriptional signature induced by MEK inhibition. When combined, loss of CDK8 or CCNC prevents the compensatory upregulation of pro-growth gene expression induced by MEK inhibition. These findings propose a new therapeutic combination for RAS-mutant neuroblastoma and may have clinical relevance for other RAS-driven malignancies.
2023-02-22 | GSE190178 | GEO
Project description:Antagonism of IAPs enhances CAR T cell efficacy
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Project description:Pluripotent stem cells (PSCs) can transition between cell states in vitro, closely reflecting developmental changes in the early embryo. PSCs can be stabilized in their naive state by blocking extracellular differentiation stimuli, particularly FGF5 MEK signaling. Here, we report that multiple features of the naive state in human and mouse PSCs can be recapitulated without affecting FGF-MEK-signaling. Mechanistically, chemical inhibition of CDK8 and CDK19 kinases (CDK8/19i) removes their ability to repress the Mediator complex at enhancers. Thus CDK8/19i increases Mediator-driven recruitment of RNA Pol II to promoters and enhancers. This efficiently stabilizes the naive transcriptional program, and confers resistance to enhancer perturbation by BRD4 inhibition. Moreover, naive pluripotency during embryonic development coincides with reduction in CDK8/19. We conclude that global hyperactivation of enhancers drives naive pluripotency, and this can be captured in-vitro by inhibiting extracellular FGF-MEK-signaling, or downstream, by CDK8/19i. These principles may apply to other contexts of cellular plasticity.
2021-05-06 | GSE152378 | GEO
Project description:Pluripotent stem cells (PSCs) can transition between cell states in vitro, closely reflecting developmental changes in the early embryo. PSCs can be stabilized in their naive state by blocking extracellular differentiation stimuli, particularly FGF5 MEK signaling. Here, we report that multiple features of the naive state in human and mouse PSCs can be recapitulated without affecting FGF-MEK-signaling. Mechanistically, chemical inhibition of CDK8 and CDK19 kinases (CDK8/19i) removes their ability to repress the Mediator complex at enhancers. Thus CDK8/19i increases Mediator-driven recruitment of RNA Pol II to promoters and enhancers. This efficiently stabilizes the naive transcriptional program, and confers resistance to enhancer perturbation by BRD4 inhibition. Moreover, naive pluripotency during embryonic development coincides with reduction in CDK8/19. We conclude that global hyperactivation of enhancers drives naive pluripotency, and this can be captured in-vitro by inhibiting extracellular FGF-MEK-signaling, or downstream, by CDK8/19i. These principles may apply to other contexts of cellular plasticity.
2020-02-26 | GSE127186 | GEO
Project description:Purpose: The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. The current study has used multi-omics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance. Experimental Design: Mass spectrometry-based proteomics and RNA-Seq was used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo xenograft models of uveal melanoma. Results: We identified a number of putative escape pathways that were upregulated following MEK inhibition including the PI3K/AKT pathway, ROR1/2 and IGF1R signaling. MEK inhibition was also associated with a widespread increase in GPCR expression, particularly the Endothelin B receptor and that this contributed to therapeutic escape through YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo xenograft studies revealed the MEK-HDAC inhibitor combination to outperform either agent alone, leading to a long-term decrease of tumor growth and the suppression of adaptive PI3K/AKT and YAP signaling. Conclusions Together our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in uveal melanoma.
2020-05-26 | PXD013988 | Pride
Project description:Cytokines are highly pleiotropic ligands that critically contribute to a balanced immune response. We have an incomplete understanding of how cytokines elicit their functional pleiotropy, which has limited their therapeutic efficacy. Here, using Interleukin-6 (IL-6) as a model system, we have performed detailed phosphoproteomic and transcriptomic studies in human CD4 + T helper (Th)-1 cells to address the molecular bases defining cytokine functional pleiotropy. We have identified cyclin dependent kinase (CDK)8 as a new negative regulator of transcriptional activities of signal transducer and activator of transcription (STAT)3. We found that CDK8 is a major regulator of the IL-6 phosphoproteome and interacts with STAT3 in the nucleus upon IL-6 stimulation. Inhibition of CDK8 activity, using specific small molecules inhibitors, reduced the IL-6-induced phosphoproteome by 23% in Th-1 cells, including STAT3 S727 phosphorylation. STAT3 binding to target DNA sites in the genome was increased upon CDK8 inhibition, which resulted in a concomitant increase in STAT3 mediated transcriptional activity. Importantly, inhibition of CDK8 activity under Th-17 polarizing conditions resulted in an enhancement of Th-17 differentiation. Our results support a model where CDK8 regulates STAT3 transcriptional processivity via modulation of its gene loci resident time, critically contributing to diversification of IL-6 responses.
2020-12-23 | PXD020964 | Pride
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Project description:Combined Inhibition of Gaq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma
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Project description:RNAseq is performed (50bp single end reads) on parental young adult mouse intestinal cells (YAMC) or two clones in which Cdk8 allele is ablated using CRISPR Examination of transcriptomic changes after knockout of Cdk8 using CRISPR. Two clones of Cdk8 knockouts are compared to parental YAMC cells
2015-07-31 | E-GEOD-71385 | biostudies-arrayexpress