Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: A time-course RNA-seq experiment testing the effect of drug treatment using selective CDK9 inhibitor AZD4573. The experiment was done using a pancreatic cancer cell line HPAF-II carrying KRAS G12D mutation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270409 | GEO | 2024/08/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Unraveling the CDK9/PP2A/ERK Network in Transcriptional Pause Release and Complement Activation in KRAS-mutant Cancers.

Project description:Selective inhibition of the transcription elongation factor (P-TEFb) complex represents a promising approach in cancer therapy, yet CDK9 inhibitors (CDK9i) are currently limited primarily to certain hematological malignancies. Herein, while initial responses to CDK9-targeted therapies are observed in vitro across various KRAS-mutant cancer types, their efficacy is far from satisfactory in nude mouse xenograft models. Mechanistically, CDK9 inhibition leads to compensatory activation of ERK-MYC signaling, accompanied by the recovery of proto-oncogenes, upregulation of immediate early genes (IEGs), stimulation of the complement C1r-C3-C3a cascade, and induction of tumor immunosuppression. The "paradoxical" regulation of PP2Ac activity involving the CDK9/Src interplay contributes to ERK phosphorylation and pause-release of RNA polymerase II (Pol II). Co-targeting of CDK9 and KRAS/MAPK signaling pathways eliminates ERK-MYC activation and prevents feedback activation mediated by receptor tyrosine kinases, leading to more effective control of KRAS-mutant cancers and overcoming KRASi resistance. Moreover, modulating the tumor microenvironment (TME) by complement system intervention enhances the response to CDK9i and potently suppresses tumor growth. Overall, the preclinical investigations establish a robust framework for conducting clinical trials employing KRASi/SOS1i/MEKi or immunomodifiers in combination with CDK9i to simultaneously target cancer cells and their crosstalk with the TME, thereby yielding improved responses in KRAS-mutant patients.

| S-EPMC11538672 | biostudies-literature

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: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.

2019-11-08 | GSE129012 | GEO

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 the Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to assess genome-wide chromatin accessibility in two DLBCL cell lines, OCI-LY3 and VAL, treated with AZD4573 (30 nM) at 0, 3, and 8 hours. We found that CDK9 inhibition led to gain and loss of accessible chromatin genome-wide, with enrichment of CTCF/BORIS motifs in decreased accesibility regions.

2022-03-21 | GSE198851 | GEO

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).

2020-05-26 | PXD013796 | Pride

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.

2022-08-05 | GSE210372 | GEO

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 is a Dependency in GATA-3 driven and MCL-1 independent T-cell Lymphomas [RNA-seq]

Project description:The transcription factor GATA-3 is a proto-oncogene in subsets of mature T cell lymphomas (TCL). CDK9 is a transcriptional regulator that, by phosphorylating paused RNA polymerase II (RNAPII), enables efficient transcriptional elongation. Therefore, we were motivated to examine the extent to which CDK9 is required for controlling transcription and expression of GATA-3 and its target genes. A pharmacologic strategy, using the selective CDK9 inhibitor AZD4573, was utilized to identify CDK9 dependent transcripts. Traveling ratios, defined as the ratio of RNAPII bound at promoter to RNAPII bound within the gene body, were determined by RNAPII ChIP-seq in cell treated with AZD4573 (or vehicle control). CDK9 dependent genes were defined as those with increased traveling ratio and decreased transcripts. MCL-1 dependency was determined in these cell lines by BH3 profiling. The extent to which CDK9 inhibition transcriptionally reprograms TCL was further examined in complementary ex vivo and in vivo studies using primary TCL specimens and GEM and PDX models

2025-11-28 | GSE296506 | GEO

CDK9 is a Dependency in GATA-3 driven and MCL-1 independent T-cell Lymphomas [ChIP-seq]

2025-11-28 | GSE296537 | GEO

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

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

| PRJNA1126316 | ENA