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Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that can be Exploited by Targeting DNA Polymerase Epsilon

ABSTRACT: Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that can be Exploited by Targeting DNA Polymerase Epsilon

PROVIDER: PRJNA667486 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12775267.fastq.gz	Fastqsanger.gz
	SRR12775268.fastq.gz	Fastqsanger.gz
	SRR12775269.fastq.gz	Fastqsanger.gz
	SRR12775270.fastq.gz	Fastqsanger.gz
	SRR12775271.fastq.gz	Fastqsanger.gz

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Similar Datasets

Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that Can Be Exploited by Targeting DNA Polymerase ε.

Project description:Knowledge of fundamental differences between breast cancer subtypes has driven therapeutic advances; however, basal-like breast cancer (BLBC) remains clinically intractable. Because BLBC exhibits alterations in DNA repair enzymes and cell-cycle checkpoints, elucidation of factors enabling the genomic instability present in this subtype has the potential to reveal novel anti-cancer strategies. Here, we demonstrate that BLBC is especially sensitive to suppression of iron-sulfur cluster (ISC) biosynthesis and identify DNA polymerase epsilon (POLE) as an ISC-containing protein that underlies this phenotype. In BLBC cells, POLE suppression leads to replication fork stalling, DNA damage, and a senescence-like state or cell death. In contrast, luminal breast cancer and non-transformed mammary cells maintain viability upon POLE suppression but become dependent upon an ATR/CHK1/CDC25A/CDK2 DNA damage response axis. We find that CDK1/2 targets exhibit hyperphosphorylation selectively in BLBC tumors, indicating that CDK2 hyperactivity is a genome integrity vulnerability exploitable by targeting POLE.

| S-EPMC7687292 | biostudies-literature

Hyperactive CDK2 Activity in Basal-like Breast Cancer Imposes a Genome Integrity Liability that can be Exploited by Targeting DNA Polymerase Epsilon

Project description:RNAseq data for MDA-MB-231, CAMA-1, and MCF7 cells expressing shPOLE and either a vector control or cDNA POLE rescue

2020-10-06 | GSE159052 | GEO

Inactivation of CDK2 is synthetic lethal to MYCN-overexpressing cancer cells

Project description:Two genes have a synthetic lethal relationship when silencing or inhibition of one gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetic lethal to neuroblastoma cells with MYCN amplification and overexpression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by three RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53 and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with Roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetic lethal relation between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. CDK2 shRNA in a tet repressor system was stably transfected in the IMR32 cell line. Time course analysis was performed in triplicate after induction of CDK2 shRNA at 5 time points.

2014-05-19 | E-GEOD-16480 | biostudies-arrayexpress

CDK2-mediated TNFa Upregulation as a Mechanism of Cytotoxicity in Acute Leukemia

Project description:Although inhibitors of the kinases CHK1, ATR and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines, including TP53 null acute myeloid leukemia (AML) and BCR/ABL-positive acute lymphoid leukemia (ALL), in vitro and inhibits leukemic colony formation in clinical AML samples ex vivo. In further studies, CHK1 downregulation or CHK1 inhibitor treatment triggered signaling in sensitive human acute leukemia cell lines that involved CDK2 activation followed by AP1-dependent TNF transactivation, TNF production and engagement of a TNFR1- and BID-dependent apoptotic pathway. AML lines that were intrinsically CHK1 inhibitor resistant exhibited high CHK1 expression and were sensitized by CHK1 downregulation. Signaling through this same CDK2  AP1  TNF cytotoxic pathway was also initiated by ATR or WEE1 inhibitors in vitro and during CHK1 inhibitor treatment of AML xenografts in vivo. Collectively, these observations not only identify new contributors to antileukemic cell action of CHK1, ATR and WEE1 inhibitors, but also delineate a previously undescribed pathway leading from aberrant CDK2 activation to death ligand-induced killing that can potentially be exploited for acute leukemia treatment.

2020-12-28 | GSE131912 | GEO

CDK2 depletion effect on human myeloid cell line undergoing differentiation

Project description:Analysis of NB4 myeloid cells depleted for CDK2. Results provide insight into the role of CDK2 in myeloid cell differentiation. We used microarrays to detail the global programme of gene expression underlying CDK2-depletion induced differentiation and identified distinct classes of up-regulated genes during this process.

2018-12-31 | GSE64077 | GEO

Inactivation of CDK2 is synthetic lethal to MYCN-overexpressing cancer cells

2014-05-19 | GSE16480 | GEO

Human HCT-116 cells: Control vs CDK2 knockout, NU6102 treated and resistant cells

Project description:Transcriptional profiling of isogenic human colorectal cancer cell line HCT-116, comparing parental cells, CDK2 knockout cells, cells treated with the CDK2-selective inhibitor NU6102 and cells resistant to 50µM NU6102. The aim was to compare effects of loss of CDK2 gene or kinase activity and determine potential mechanisms of inhibitor-resistance

2017-08-03 | GSE102165 | GEO

Halolamina pelagica strain:CDK2

Project description:Halolamina pelagica strain:CDK2 Genome sequencing and assembly

| PRJNA272888 | ENA

Transcriptomic expression of A549 CDK2 KO cells treated or untreated with palbociclib

Project description:Inducing senescence in cancer cells is emerging as a new therapeutic strategy. We tested the senescence induction of palbociclib in CDK2 KO cells, and profiled these for senescence associated gene signatures. This was a CRISPR generated CDK2 KO clone in A549 cells.

2022-03-03 | GSE197600 | GEO

Copy number analysis of OVCAR-3 and CDK2 resistant sublines

Project description:Cyclin E1 (CCNE1) is amplified in various tumor types including high-grade serous ovarian cancer where it is associated with poor clinical outcome. We have demonstrate that suppression of the Cyclin E1 partner kinase, CDK2, induces apoptosis in a CCNE1 amplicon-dependent manner. Little is known of mechanisms of resistance to CDK inhibitors. We therefore generated OVCAR-3 sublines with reduced sensitivity to CDK2 inhibitors and profiled by SNP copy number microarrays. Arrayed samples included parental OVCAR-3 cells and five independently derived sublines resistant to PHA-533533 (OVCAR3-533533-R1, -R3, -R5, -R6, -R7). The resistant cell lines were arrayed after drug selection (P5).

2013-09-01 | E-GEOD-48920 | biostudies-arrayexpress

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