Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition

ABSTRACT: Excessive genomic instability coupled with abnormalities in DNA repair pathways induce high levels of “replication stress” when cancer cells propagate. Rather than hampering cancer cell proliferation, novel treatment strategies are turning their attention toward targeting cell cycle checkpoint kinases (such as ATR, CHK1, WEE1 and others) along the DNA damage response and replicative stress response pathways, thereby allowing unrepaired DNA damage to be carried forward towards mitotic catastrophe and apoptosis. The selective inhibitor of ATR kinase elimusertib (BAY 1895344), has demonstrated preclinical and clinical monotherapy activity; however, reliable predictive biomarkers of treatment benefit are still lacking. In this study, using gene expression profiling of 24 cell lines from different cancer types and in a panel of ovarian cancer cell lines, we found that nuclear-specific enrichment of checkpoint kinase 1 (CHK1) correlated with increased sensitivity to elimusertib. Using an advanced multispectral imaging system in subsequent cell line-derived xenograft specimens, we showed a trend between nuclear phosphorylated-CHK1 (pCHK1) staining and increased sensitivity to the ATR inhibitor elimusertib, indicating the potential value of pCHK1 expression as a predictive biomarker of ATR inhibitor sensitivity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217579 | GEO | 2022/11/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress

Project description:While effective anti-cancer drugs targeting the CHK1 kinase are advancing in the clinic, drug resistance is rapidly emerging. Here, we demonstrate that CRISPR-mediated knockout of the little-known gene FAM122A confers cellular resistance to CHK1 inhibitors and cross-resistance to ATR inhibitors. Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase which dephosphorylates the WEE1 protein and rescues WEE1 from Ubiquitin-mediated degradation. The resulting increase in WEE1 protein expression reduces replication stress, activates the G2/M checkpoint, and confers cellular resistance to CHK1 inhibitors. Interestingly, in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. A combination of a CHK1 inhibitor plus a WEE1 inhibitor can overcome CHK1 inhibitor resistance of these tumor cells, thereby enhancing anti-cancer activity. The FAM122A expression level in a tumor cell can serve as a useful biomarker for predicting CHK1 inhibitor sensitivity or resistance.

2021-01-01 | GSE158338 | GEO

SETD2 loss and ATR inhibition synergistically promote cGAS signaling and immunotherapy response in renal cell carcinoma

Project description:Immune checkpoint blockade (ICB) demonstrates durable clinical benefit only in a minority of renal cell carcinoma (RCC) patients. Identifying molecular features that determine response and developing approaches to enhance the response remain an urgent clinical need. Here we found that, in multiple RCC cell lines, targeting the ATR-CHK1 axis with pharmacological inhibitors increased cytosolic DNA accumulation, activated the cGAS-IRF3-dependent cytosolic DNA sensing pathway, and resulted in the inflammatory cytokine expression. SETD2 mutated RCC cell lines or tumor samples were associated with preferential ATR-CHK1 activation over ATM-CHK2 activation. SETD2 knockdown promoted the cytosolic DNA sensing pathway and conferred greater sensitivity in response to ATR-CHK1 inhibition. In murine Renca tumors, Setd2 knockdown and ATR inhibitor VE822 synergistically promoted cytosolic DNA sensing pathway, immune cell infiltration, and immune checkpoint protein expression. Setd2 deficient Renca tumors demonstrated greater vulnerability to ICB monotherapy or in combination with VE822 than Setd2 proficient tumors. SETD2 mutations were associated with a higher response rate and prolonged overall survival in ICB-treated RCC patients, but not in non-ICB-treated RCC patients. This study provides a mechanism-based guidance to develop more personalized combination therapy regimens for RCC patients with SETD2 mutations.

2023-07-25 | GSE234732 | GEO

Oncogenic RAS sensitizes cells to drug-induced replication stress via transcriptional silencing of P53

Project description:Since oncogenes induce DNA replication stress (RS), cancer cells rely on the intra S-phase checkpoint for survival. Consequently, RS inducing drugs and ATR and CHK1 inhibitors are exploited as anti-cancer therapy. However, drug resistance limits efficient use. This raises the question what determines sensitivity of individual cancer cells to RS. Here, we report that oncogenic RAS dampens the P53 checkpoint which confers sensitivity to RS. We demonstrate that inducible expression of HRASG12V leads to mild RS in RPE-hTERT cells and was sufficient to sensitize cells to ATR and CHK1 inhibitors. Using RNA-sequencing we discovered that P53 signaling is essential for the response to RS. However, oncogenic RAS attenuates transcription of P53 and its target genes. Accordingly, live cell imaging shows that HRASG12V exacerbates RS in S/G2-phase. Thus, our results suggest that hyperactivation of the MAPK pathway could predict durable responses to RS inducing drugs in cancer patients

2022-04-05 | GSE168987 | GEO

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

Phosphoproteomics analysis of CHK1 inhibitor treatment

Project description:Inhibitors of checkpoint kinase 1 (CHK1),a central component of DNA damage and cell cycle checkpoint response, represent a promising new cancer therapy, but the global cellular functionsthey regulate through phosphorylationare poorly understood. To elucidate the CHK1-regulated phosphorylation network, we performed a global quantitative phosphoproteomics analysis, which revealed 142 phosphositeswhose phosphorylation levels were significantly different following treatment with the CHK1 inhibitor SCH 900776.

2020-04-23 | PXD015125 | Pride

f756ebf7-f273-4fec-a8ba-1463bcdc061d - samples

Project description:CSC DDR dataset contains 4 bam files of two pairs of colorectal CSCs sensitive and resistant to ATR or CHK1 inhibitor

| EGAD00001006774 | EGA

A pan-cancer transcriptome analysis to identify the molecular mechanism of prexasertib resistance [microarray]

Project description:The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and in vivo models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms which protect cells from oncogene-induced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity. We included microarray data here as part of the study. RNAseq data was uploaded separately.

2020-02-24 | GSE143007 | GEO

A pan-cancer transcriptome analysis to identify the molecular mechanism of prexasertib resistance_RNASeq

Project description:The combined influence of oncogenic drivers, genomic instability, and/or DNA damage repair deficiencies increases replication stress in cancer. Cells with high replication stress rely on the upregulation of checkpoints like those governed by CHK1 for survival. Previous studies of the CHK1 inhibitor prexasertib demonstrated activity across multiple cancer types. Therefore, we sought to (1) identify markers of prexasertib sensitivity and (2) define the molecular mechanism(s) of intrinsic and acquired resistance using preclinical models representing multiple tumor types. Our findings indicate that while cyclin E dysregulation is a driving mechanism of prexasertib response, biomarkers associated with this aberration lack sufficient predictive power to render them clinically actionable for patient selection. Transcriptome analysis of a pan-cancer cell line panel and in vivo models revealed an association between expression of E2F target genes and prexasertib sensitivity and identified innate immunity genes associated with prexasertib resistance. Functional RNAi studies supported a causal role of replication fork components as modulators of prexasertib response. Mechanisms which protect cells from oncogene-induced replication stress may safeguard tumors from such stress induced by a CHK1 inhibitor, resulting in acquired drug resistance. Furthermore, resistance to prexasertib may be shaped by innate immunity. We included RNASseq data here as part of the study. Microarray data was uploaded separately.

2020-02-05 | GSE143152 | GEO

Expression data of ATM, ATR, CHK1, CHK2, and 53BP1 shRNA knockdown and control shRNA in MCF-10A cells

Project description:Homologous recombination-mediated DNA repair deficiency (HRD) predisposes to cancer development, but also provides therapeutic opportunities. Here, we identified an HRD gene signature that robustly predicted HRD status. Unexpectedly, concurrent loss of PTEN in BRCA1-deficient cells might extensively rewire the HR repair network and confer resistance to PARP inhibitor, partially through over-expression of TTK. We used the HRD gene signature as a drug discovery tool and found several PARP-inhibitor-synergizing agents through the connectivity map. Thus gene expression profiling can be used to define the functional status of the HR repair network providing prognostic and therapeutic information. Various shRNAs that target genes involved in homologous recombination (HR) were transfected in MCF-10A non-transformed breast cells lines. Stable HR gene knockdown MCF-10A cells were seeded 200000 at 10 cm plate. Cells were harvested after 48 hours culturing and used for gene expression profiling. The shRNAs that target ATM, ATR, CHK1, CHK2, and 53BP1 genes were transfected in MCF-10A non-transformed breast cell line by lentiviral particles and selected stable ATM, ATR, CHK1, CHK2, and 53BP1 knockdown MCF-10A cells. Scrambled control shRNA-transfected and wild type MCF-10A cells were applying as control. All knockdown and control MCF-10A cells were seeded with 2 x 10^5 cells at 10 cm culture plate. Cells were cultured in MCF-10A medium and harvested after 48 hours culturing. mRNA was extracted from collected cells and performing gene expression profiling. Three biological replicates were applied.

2014-01-24 | E-GEOD-54268 | biostudies-arrayexpress

The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity

Project description:Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i’s) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.

2024-04-04 | GSE263176 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data