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RNA-seq data corresponding to: AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells

ABSTRACT: A time-course RNA-seq experiment testing the effect of drug treatment using selective CDK9 inhibitor AZD4573. The experiment was done using a resistant cell-line to AZD4573: the MCF7 breast cancer cell-line.

ORGANISM(S): Homo sapiens

PROVIDER: GSE129012 | GEO | 2019/11/08

REPOSITORIES: GEO

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AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells

Project description:Phosphorylation of RNA polymerase II by cyclin-dependent kinase 9 (CDK9) is crucial for transcriptional regulation, and acute inhibition of CDK9 results in the rapid downregulation of genes with short-lived transcripts and labile proteins. Multiple non-selective CDK9 inhibitors have progressed clinically but were limited by a narrow therapeutic window. This work describes a novel, potent, and highly selective CDK9 inhibitor, AZD4573. Using integrated transcriptomic and proteomic analyses, loss-of-function pathway interrogation, and pharmacological comparisons, Mcl-1 depletion was identified as a major mechanism through which AZD4573 induces cell death in tumor cells. AZD4573 suppresses Mcl-1 in a dose- and time-dependent manner that causes caspase-3 cleavage in sensitive cancer cells, most notably in hematological malignancies. This pharmacodynamic response is observed in vivo as well, which leads to regressions in both subcutaneous tumor xenografts and disseminated models at tolerated doses as monotherapy or in combination with venetoclax. Fully understanding the mechanism, exposure, and anti-tumor activity of AZD4573 also informed the development of a robust PK/PD/efficacy model that helped select and predict the starting and efficacious dose range in man. Accordingly, AZD4573 is currently being evaluated in a phase I clinical trial for patients with hematological malignancies (clinicaltrials.gov identifier: NCT03263637).

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Unraveling the CDK9/PP2A/ERK network in transcriptional pause release and complement activation in KRAS-mutant cancers

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RNA-seq data corresponding to: AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells

Project description:RNA-seq data corresponding to: AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells

| PRJNA529703 | ENA

CDK9 inhibition with AZD4573 in DLBCL

Project description:CDK9 inhibition with AZD4573 in DLBCL

| PRJNA865376 | ENA

CDK9 inhibition with AZD4573 in DLBCL

Project description:CDK9 inhibition with AZD4573 in DLBCL

| PRJNA817183 | ENA

CDK9 inhibition with AZD4573 in DLBCL

Project description:We report the effects of CDK9 inhibition (AZD4573) on the epigenetic landscape in Diffuse Large B-cell Lymphoma (DLBCL). This study utilized chromatin immunoprecipitation with massively parallel DNA sequencing (ChIP-seq) to assess genome-wide post-translational histone modifications (H3K27ac and H3K4me3) and DNA occupancy of transcriptional proteins (RNAPII and BRD4) in two DLBCL cell lines, OCI-LY3 and VAL, treated with the CDK9 inhibitor AZD4573 (30 nM). Cells were treated for 0, 3 and 8 hours prior to harvest. After 8-hour exposure, drug was washed out and cells were harvested after 24 hours. We found that CDK9 inhibition led to an increase in RNAPII promoter proximal pausing, and increase in BRD4 enrichment on the promoter, and a decrease in promoter H3K4me3. Treatment induced reprograming of the super-enhancer landscape including loss of super-enhancers next to genes in oncogenic pathways.

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Expression profiling of HeLa cell line treated with CDK9 inhibitor

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