ATR/Chk1 interacting lncRNA modulates DNA damage response to induce breast cancer chemoresistance
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PROVIDER: PRJNA913421 | ENA |
REPOSITORIES: ENA
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Project description:The ATR-Chk1 pathway is essential in cellular responses to DNA damage and replication stress, whereas the role of long noncoding RNAs (lncRNAs) in regulating this pathway remains largely unknown. In this study, we identify an ATR and Chk1 interacting lncRNA (ACIL, also known as LRRC75A-AS1 or SNHG29), which promotes the phosphorylation of Chk1 by ATR upon DNA damages. High ACIL levels are associated with chemoresistance to DNA damaging agents and poor outcome of breast cancer patients. ACIL knockdown sensitizes breast cancer cells to DNA damaging drugs in vitro and in vivo. ACIL protects cancer cells against DNA damages by inducing cell cycle arrest, stabilizing replication forks and inhibiting unscheduled origin firing, thereby guarding against replication catastrophe and contributing to DNA damage repair. These findings demonstrate a lncRNA-dependent mechanism of activating the ATR-Chk1 pathway and highlight the potential of utilizing ACIL as a predictive biomarker for chemotherapy sensitivity, as well as targeting ACIL to reverse chemoresistance in breast cancer.
| S-EPMC11325286 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-07-16 | GSE221222 | GEO
Project description:Disease frameshift mutations of calreticulin (CALR) are the second most prevalent driver mutations in essential thrombocythemia (ET) and primary myelofibrosis (PMF). To identify potential targeted therapies for CALR mutated myeloproliferative neoplasms, we aimed to search for small molecule drugs that selectively inhibit the growth of CALR mutated cells using high-throughput drug screening. We investigated 89,172 compounds using isogenic cell lines and identified several hits targeting the ATR-CHK1 pathway. The selective inhibitory effect of these candidate compounds was validated in a co-culture assay of CALR mutated and wild type cells. Of the tested hit compounds, CHK1 inhibitors potently depleted CALR mutated cells, allowing CALR wild type cell dominance in the co-culture over time. Neither CALR deficient cells nor JAK2V617F mutated cells showed hypersensitivity to the drug treatment, suggesting that the vulnerability to ATR-CHK1 inhibition is specifically caused by the oncogenic activation by the mutant CALR. CHK1 inhibitors induced replication stress in CALR mutated cells revealed by elevated pan-nuclear staining for γH2AX and hyperphosphorylation of RPA2. They also promoted S-phase cell cycle arrest and blocked the completion of DNA replication in CALR mutated cells. Transcriptomic and phosphoproteomic analyses revealed a replication stress signature caused by the oncogenic CALR mutation, suggesting an intrinsic vulnerability of these cells to CHK1 perturbation. This study indicates that ATR-CHK1 pathway is a potential therapeutic target in CALR mutated hematopoietic cells.
2021-09-07 | PXD026803 | Pride
Project description:ATR/CHK1/WEE1 dependency in SRSF2-mutated myeloid malignancies
| PRJNA878761 | ENA
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
Project description: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.
2022-11-09 | GSE217579 | GEO
Project description:The cell division cycle is tightly controlled in normal cells. Cancer cells are characterized by deregulation in cell division cycle, which is associated with increased DNA replication and elevated cellular proliferation. Recently, genetic studies indicate that cyclin dependent kinases CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle, instead, they are only required for the proliferation of specific cell types.Thus, targeting the activities of CDK2, CDK4 and CDK6 may be a promising approach for cancer treatment. Rocaglamides (Roc) (= Flavaglines), derived from the traditional Chinese medicinal plant Aglaia, are a group of naturally occurring herbal chemicals characterized by a cyclopenta[b]benzofurans skeleton. A number of Roc derivatives have been found to have potent inhibitory effects on tumor growth with IC50 concentrations at the nM rages. Roc-mediated inhibition of proliferation was first found to be associated with inhibition of protein synthesis in 1998. In this study, using the representative Roc-A compound we revealed a novel mechanistic function of Roc. We show that Roc-A induces rapid activation of ATM (ataxiatelangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) kinases. Activated ATM and ATR in turn activate the downstream checkpoint kinases CHK1 and CHK2. The latter then phosphorylate Cdc25A that leads to a phosphorylation-mediated degradation of Cdc25A. Usually, ATR and ATM are activated in response to DNA damage. However, in this study we show that Roc-A does not directly induce DNA breaks. To elucidate the molecular mechanism by which Roc-A activates ATM and ATR we performed a time-resolved microarray analysis to compare Roc-A-inducible genes in malignant vs. normal T lymphocytes. Based on the dynamic gene responses we found that Roc-A stimulates in Jurkat, but not in normal T lymphocytes, a set of genes responsive to DNA damage and nucleotide excision repair. This finding provides a hint of the molecular bases for Roc-induced activation of ATM and ATR. This finding also revealed a new scope for cancer treatment using Roc-A. The isolation time points for Roc A treated D6 T-cells were recorded at t=[1,2,3,4,6,8,10,14,20,28,36] hours after stimulation. Post-stimulation time points for Jurkat cells are t=[0.5,1,2,3,4,5,6,7,8,10,12,14,16,20,24,28,32,36]. Unstimulated control time points were taken at t=[0,4,10,16,24,36] hours for Jurkat cells at t=[0,6,14,24,36] hours.
2013-10-12 | E-GEOD-41072 | biostudies-arrayexpress
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
Project description:The cell division cycle is tightly controlled in normal cells. Cancer cells are characterized by deregulation in cell division cycle, which is associated with increased DNA replication and elevated cellular proliferation. Recently, genetic studies indicate that cyclin dependent kinases CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle, instead, they are only required for the proliferation of specific cell types.Thus, targeting the activities of CDK2, CDK4 and CDK6 may be a promising approach for cancer treatment. Rocaglamides (Roc) (= Flavaglines), derived from the traditional Chinese medicinal plant Aglaia, are a group of naturally occurring herbal chemicals characterized by a cyclopenta[b]benzofurans skeleton. A number of Roc derivatives have been found to have potent inhibitory effects on tumor growth with IC50 concentrations at the nM rages. Roc-mediated inhibition of proliferation was first found to be associated with inhibition of protein synthesis in 1998. In this study, using the representative Roc-A compound we revealed a novel mechanistic function of Roc. We show that Roc-A induces rapid activation of ATM (ataxiatelangiectasia mutated) and ATR (ataxia-telangiectasia and Rad3-related) kinases. Activated ATM and ATR in turn activate the downstream checkpoint kinases CHK1 and CHK2. The latter then phosphorylate Cdc25A that leads to a phosphorylation-mediated degradation of Cdc25A. Usually, ATR and ATM are activated in response to DNA damage. However, in this study we show that Roc-A does not directly induce DNA breaks. To elucidate the molecular mechanism by which Roc-A activates ATM and ATR we performed a time-resolved microarray analysis to compare Roc-A-inducible genes in malignant vs. normal T lymphocytes. Based on the dynamic gene responses we found that Roc-A stimulates in Jurkat, but not in normal T lymphocytes, a set of genes responsive to DNA damage and nucleotide excision repair. This finding provides a hint of the molecular bases for Roc-induced activation of ATM and ATR. This finding also revealed a new scope for cancer treatment using Roc-A.
2013-10-12 | GSE41072 | GEO
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