Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition
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PROVIDER: PRJNA899576 | ENA |
REPOSITORIES: ENA
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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:Despite advances in multi-modal treatment approaches, clinical outcomes of patients suffering from PAX3-FOXO1 fusion oncogene-expressing alveolar rhabdomyosarcoma (ARMS) remain dismal. Here we show that PAX3-FOXO1-expressing ARMS cells are sensitive to pharmacological ataxia telangiectasia and Rad3 related protein (ATR) inhibition. Expression of PAX3-FOXO1 in muscle progenitor cells is not only sufficient to increase sensitivity to ATR inhibition, but PAX3-FOXO1-expressing rhabdomyosarcoma cells also exhibit increased sensitivity to structurally diverse inhibitors of ATR. Mechanistically, ATR inhibition leads to replication stress exacerbation, decreased BRCA1 phosphorylation and reduced homologous recombination-mediated DNA repair pathway activity. Consequently, ATR inhibitor treatment increases sensitivity of ARMS cells to PARP1 inhibition in vitro, and combined treatment with ATR and PARP1 inhibitors induces complete regression of primary patient-derived ARMS xenografts in vivo. Lastly, a genome-wide CRISPR activation screen (CRISPRa) in combination with transcriptional analyses of ATR inhibitor resistant ARMS cells identifies the RAS-MAPK pathway and its targets, the FOS gene family, as inducers of resistance to ATR inhibition. Our findings provide a rationale for upcoming biomarker-driven clinical trials of ATR inhibitors in patients suffering from ARMS.
2022-07-11 | PXD035131 | JPOST Repository
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2008-04-01 | E-MEXP-1329 | biostudies-arrayexpress
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
Project description:Microcephaly and medulloblastoma result from mutations that compromise genomic stability. We report that Atr, which is mutated in the microcephalic disorder Seckel syndrome, is required to maintain chromosomal integrity during postnatal cerebellar neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis, and cerebellar hypoplasia. Co-deletions of either Bax and Bak or p53 prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. Atr-deficient CGNPs showed impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to Atr-deficient proliferation was p53-driven. Acute Atr inhibition in vivo by nanoparticle-formulated VE-822 reproduced the disruptions seen with Atr deletion. Our data show that p53-driven apoptosis and senescence, and non-apoptotic cell death redundantly limit growth in Atr-deficient progenitors. These overlapping mechanisms that suppress growth in Atr-disrupted CGNPs may be exploited for treatment of CGNP-derived medulloblastoma using Atr inhibition.
2016-09-01 | GSE85393 | GEO
Project description:Proteasome inhibitors are important chemotherapeutics in the treatment of multiple myeloma, but they are currently used empirically as no markers of sensitivity have been validated. We have identified expression of tight junction protein (TJP) 1 as being associated with sensitivity of plasma cells in vitro and in vivo to proteasome inhibitors. TJP1 suppressed expression of genes in the major histocompatibility class II region, including two catalytically active immunoproteasome subunits, thereby decreasing proteasome activity, a critical determinant of proteasome inhibitor sensitivity. This occurred through suppression by TJP1 of signaling through the epidermal growth factor receptor/Janus kinase 1/signal transducer and activator of transcription 3 pathway. In the clinic, high TJP1 expression in myeloma patients was associated with a significantly higher likelihood of responding to bortezomib, and with a longer time-to-progression after treatment. Taken together, these data support the use of TJP1 as a biomarker of sensitivity and resistance to proteasome inhibitors. To further elucidate mechanisms of bortezomib resistance, we developed human-derived multiple myeloma cell lines with a 4-fold or greater resistance to bortezomib. Then total RNA for bortezomib resistant (BR) and wild type (WT) was extracted and used for comparison by gene expression profiling.
2015-12-31 | E-GEOD-52369 | biostudies-arrayexpress
Project description:Microcephaly and medulloblastoma result from mutations that compromise genomic stability. We report that Atr, which is mutated in the microcephalic disorder Seckel syndrome, is required to maintain chromosomal integrity during postnatal cerebellar neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis, and cerebellar hypoplasia. Co-deletions of either Bax and Bak or p53 prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. Atr-deficient CGNPs showed impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to Atr-deficient proliferation was p53-driven. Acute Atr inhibition in vivo by nanoparticle-formulated VE-822 reproduced the disruptions seen with Atr deletion. Our data show that p53-driven apoptosis and senescence, and non-apoptotic cell death redundantly limit growth in Atr-deficient progenitors. These overlapping mechanisms that suppress growth in Atr-disrupted CGNPs may be exploited for treatment of CGNP-derived medulloblastoma using Atr inhibition.
2016-09-01 | GSE83720 | GEO
Project description:High-risk human papillomaviruses (HPVs) constitutively activate the ataxia telangiectasia and Rad3-related (ATR) DNA damage response pathway for their replication. Although ATR has many reported functions, knowledge of how it regulates viral replication is limited. Most studies regarding ATR function focus on its roles in cell survival and initiation of DNA damage response. In this study, we examined whether the transcriptional regulatory properties directed by ATR are critical for HPV pathogenesis, and if so which downstream targets are important. Using RNA-seq approaches, we observed that ATR knockdown increases expression of many inflammatory genes. This mechanism is dependent on the p62/GATA4 signaling pathway.
2020-07-27 | GSE142482 | GEO
Project description:Purpose:It has been shown that circular RNA (circRNA) is a key regulatory factor in development and progression of human tumors. However, the working mechanism and clinical significance of most circRNAs remain unknown in human cancer, including multiple myeloma (MM), a hematologic malignancy. Patients and methods:In the present study, high-throughput circRNA microarray was combined with bioinformatics to identify differentially expressed circRNAs in MM. The hsa_circ_0007841 expressions were shown in MM tissues of 86 patients and drug-resistant cell lines and pathological features were detected. Further, the relationship between hsa_circ_0007841 expressions in the MM tissues and pathological features of MM patients were discussed. The role of hsa_circ_0007841 as a potential biomarker and therapeutic target was analyzed. Results:Our results indicated that in MM tissues collected from patients, MM cell lines and drug-resistant cell lines, the hsa_circ_0007841 expression was significantly upregulated. A close connection with prognosis was observed. That is, hsa_circ_0007841 upregulation was correlated with chromosomal aberrations, such as gain 1q21, t(4:14) and mutations in ATR and IRF4 genes. This finding was further verified in large samples. Finally, bioinformatics analysis indicated interaction that 8 differentially expressed miRNAs and 10 candidate mRNAs interacted with hsa_circ_0007841. These results sheds new light on the basic functional research in the future. Conclusion:It was reported for the first time that hsa_circ_0007841 was significantly upregulated in MM. Our study indicated that hsa_circ_0007841 may be a novel biomarker for MM and involved in the progression of MM.
2020-04-10 | GSE133058 | GEO