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

PROVIDER: PRJNA529703 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8800820_1.fastq.gz	Fastqsanger.gz
	SRR8800820_2.fastq.gz	Fastqsanger.gz
	SRR8800812_1.fastq.gz	Fastqsanger.gz
	SRR8800812_2.fastq.gz	Fastqsanger.gz
	SRR8800813_1.fastq.gz	Fastqsanger.gz

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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).

2020-05-26 | PXD013796 | Pride

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 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

Targeting MCL-1 Causes DNA Damage and Cell Cycle Arrest Independent from Apoptosis Induction

Project description:MCL-1 is a high-priority target due to its dominant role in the pathogenesis and chemoresistance of cancer, yet clinical trials of MCL-1 inhibitors are revealing toxic side-effects. MCL-1 biology is complex, extending beyond apoptotic regulation and confounded by its multiple isoforms, domains of unknown structure and function, and challenges in distinguishing noncanonical activities from the apoptotic response. We find that, in the presence or absence of an intact mitochondrial apoptotic pathway, genetic deletion or pharmacologic targeting of MCL-1 triggers DNA damage and cell cycle arrest. Indeed, the cancer cell susceptibility profile of MCL-1 inhibitors better matches that of anti-proliferative than pro-apoptotic drugs, expanding their potential therapeutic applications, including synergistic combinations, but heightening therapeutic window concerns. Proteomic profiling across cell cycle stages provides a resource for mechanistic dissection and revealed MCM among other MCL-1-interacting nuclear protein complexes that link MCL-1 to the regulation of DNA integrity and cell cycle progression.

2025-05-06 | PXD036327 | Pride

Seletive inhibition of CDK9 in DLBCL cell lines

Project description:Deregulation of the MYC transcription factor is a key driver in lymphomagenesis. MYC induces global changes in gene expression that contribute to cell growth, proliferation and oncogenesis by stimulating the activity of RNA polymerases. A key feature in its ability to stimulate RNA Pol II activity is recruitment of pTEFb, an elongation factor whose catalytic core comprises CDK9/cyclin T complexes. Hence, MYC expression and function may be susceptible to CDK9 inhibition. Non-specific inhibitors of multiple CDKs have shown promise in B-cell malignancies, where their pro-apoptotic effect has been attributed to a reduction in transcription and downmodulation of short lived pro-survival proteins (e.g., Mcl-1). However, they lack a defined mechanism of action. Here we selectively targeted CDK9 in a pre-clinical study in DLBCL.

2018-04-13 | GSE113035 | GEO

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

Project description:CDK9 is a Dependency in GATA-3 driven and MCL-1 independent T-cell Lymphomas

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Expression profiling of HeLa cell line treated with CDK9 inhibitor

Project description:CDK9 is the kinase subunit of P-TEFb that enables RNA polymerase (Pol) II to transit from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to the lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9’s activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb’s loss of activity, only the simultaneous inhibition of CDK9 and MYC can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy. We used microarrays to examine the global impact on gene expression by imhibiting CDK9 at different time durations. HeLa cell lines treated with CDK9 inhibitor at different time points

2015-06-17 | E-GEOD-60952 | biostudies-arrayexpress

MCL‑1 is essential for hair growth by preventing BAK‑mediated apoptosis of activated adult hair follicle stem cells

Project description:Hair follicles (HFs) cycle between expansion, regression and quiescence. To investigate the role of MCL-1, a BCL-2 family protein with anti-apoptotic and non-apoptotic functions in this dynamic process, we delete Mcl-1 within the skin epithelium, using both constitutive and inducible systems. Mcl-1 deletion does not impair HF organogenesis but results in gradual hair loss and HF stem cells (HFSC) elimination. Single-cell RNA-seq profiling unveils activated DNA repair and P53 signaling pathways in HFSCs during hair regeneration. Acute Mcl-1 deletion led to the depletion of activated HFSCs. Moreover, the ERBB pathway is found to promote MCL-1 protein expression in HFs. Accordingly, ERBB inhibition depletes activated HFSCs in adult mice. Remarkably, the loss of a single Bak allele rescues Mcl-1 deletion-associated defects in both HFs and mammary glands. These findings emphasize the pivotal role of MCL-1 in inhibiting proliferation stress-induced apoptosis when quiescent stem cells re-enter cell cycling to fuel tissue regeneration.

2025-02-13 | GSE256251 | GEO

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

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

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