F756ebf7-f273-4fec-a8ba-1463bcdc061d - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001006774 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Colorectal cancer stem cells (CSCs) show heterogeneous levels of constitutive replication stress leading distinct dependence on the replication stress response. The aim of the projects was to find genetic, epigenetic, phenotypic factors associated with the resistance of colorectal CSCs to inhibitors of the ATR/CHK1 pathway, which regulates of the replication stress response. Different pairs of colorectal CSCs sensitive and resistant to ATR or CHK1 inhibitors were analyzed
| EGAS00001004892 | EGA
Project description:The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently activated in liver CSCs is NF-kB signaling. Here we evaluated the CSCs-depleting potential of NF-kB inhibition in liver cancer achieved by IKK inhibitor curcumin and specific peptide SN50 . The effects on CSCs were assessed by analysis of Side Population (SP) and expression levels of CSC-related genes as determined by RT-qPCR, gene expression microarray, EMSA, and Western blotting. Curcumin caused anti-proliferative and pro-apoptotic responses directly related to the extent of NF-kB inhibition. In curcumin-sensitive tumor cells, the treatment led to a selective CSC depletion as evidenced by a reduced SP size, decreased sphere formation, down-regulation of CSC markers and suppressed tumorigenicity. Similarly, NF-kB inhibition by SN50 caused a general suppression of cell growth accompanied by a reduced SP fraction. In contrast, curcumin-resistant cells exhibited a paradoxical increase in proliferation and expression of CSC markers. Mechanistically, CSC-depleting activity of curcumin was exerted by the NF-kB-mediated HDAC inhibition causing down-regulation of c-MYC and other key oncogenic targets. Co-administration of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin. Further, integration of a predictive signature of curcumin sensitity with our HCC database indicated that HCC patients with poor prognosis and progenitor features are most likely to benefit from NF-kB inhibition. These results demonstrate that NF-kB inhibition can specifically target CSC populations and suggest a potential for combined inhibition of NF-kB and HDAC signaling for treatment of liver cancer patients with poor prognosis. Five human hepatoma cell lines with and without curcumin
2015-12-31 | E-GEOD-59713 | biostudies-arrayexpress
Project description:Sensitive versus Resistant patient-derived colorectal cancer tumor xenografts with PIK3CA mutant against saracatinib (AZD0530) Sensitive versus Resistant patient-derived colorectal cancer tumor xenografts with PIK3CA mutant against saracatinib (AZD0530)
2012-02-24 | E-GEOD-36006 | biostudies-arrayexpress
Project description:Purpose: The importance of cellular context to the synergy of DNA Damage Response (DDR) targeted agents is important for tumors with mutations in DDR pathways, but less well-established for tumors driven by oncogenic transcription factors. In this study, we exploit the widespread transcriptional dysregulation of the EWS-FLI1 transcription factor to identify an effective DDR targeted combination therapy for Ewing Sarcoma (ES). Experimental Design: We used matrix drug screening to evaluate synergy between a DNA-PK inhibitor (M9831) or an ATR inhibitor (berzosertib) and chemotherapy. The combination of berzosertib and cisplatin was selected for broad synergy, mechanistically evaluated for ES selectivity, and optimized for in vivo schedule. Results: Berzosertib combined with cisplatin demonstrates profound synergy in multiple ES cell lines at clinically achievable concentrations. The synergy is due to loss of expression of the ATR downstream target CHEK1, loss of cell cycle checkpoints, and mitotic catastrophe. Consistent with the goals of the project, EWS-FLI1 drives the expression of CHEK1 and five other ATR pathway members. The loss of expression is not due to transcriptional repression and instead caused by degradation coupled with suppression of protein translation. The profound synergy is realized in vivo with a novel optimized schedule of this combination in subsets of ES models leading to durable complete responses in 50% of animals bearing two different ES xenografts. Conclusions: These data exploit EWS-FLI1 driven alterations in cell context to broaden the therapeutic window of berzosertib and cisplatin to establish a promising combination therapy and a novel in vivo schedule.
2024-03-13 | GSE260602 | GEO
Project description:Starting with H3122 cells, which harbor the EML4-ALK E13;A20 fusion and are known to be sensitive to ALK tyrosine kinase inhibitors, we generated isogenic pairs of ALK TKI sensitive and ALK TKI resistant cell lines using established methods (see Chmeliecki, J et al Science Trans Med 2011). We modeled resistance against the currently FDA approved ALK TKI, crizotinib (also called PF-1066). We also modeled resistance against a novel more potent ALK inhibitor, X-376 (ref: Lovly, CM et al Cancer Research 2011). We compared gene expression profiles between the 'parental' (ALK TKI sensitive) H3122 cells and the drug resistant cells (H3122 CR for Crizotinib resistant cells and H3122 XR for X-376 resistant cells).
2014-07-14 | GSE49508 | GEO
Project description:The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently activated in liver CSCs is NF-kB signaling. Here we evaluated the CSCs-depleting potential of NF-kB inhibition in liver cancer achieved by IKK inhibitor curcumin and specific peptide SN50 . The effects on CSCs were assessed by analysis of Side Population (SP) and expression levels of CSC-related genes as determined by RT-qPCR, gene expression microarray, EMSA, and Western blotting. Curcumin caused anti-proliferative and pro-apoptotic responses directly related to the extent of NF-kB inhibition. In curcumin-sensitive tumor cells, the treatment led to a selective CSC depletion as evidenced by a reduced SP size, decreased sphere formation, down-regulation of CSC markers and suppressed tumorigenicity. Similarly, NF-kB inhibition by SN50 caused a general suppression of cell growth accompanied by a reduced SP fraction. In contrast, curcumin-resistant cells exhibited a paradoxical increase in proliferation and expression of CSC markers. Mechanistically, CSC-depleting activity of curcumin was exerted by the NF-kB-mediated HDAC inhibition causing down-regulation of c-MYC and other key oncogenic targets. Co-administration of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin. Further, integration of a predictive signature of curcumin sensitity with our HCC database indicated that HCC patients with poor prognosis and progenitor features are most likely to benefit from NF-kB inhibition. These results demonstrate that NF-kB inhibition can specifically target CSC populations and suggest a potential for combined inhibition of NF-kB and HDAC signaling for treatment of liver cancer patients with poor prognosis.
2015-12-31 | GSE59713 | GEO
Project description:Glioblastoma is an aggressive and highly invasive disease that often resists treatment. Tumour cells can restrict the DNA-damaging effects of temozolomide (TMZ) and radiation therapy (RT) using the DNA damage response (DDR) mechanism which activates cell cycle arrest and DNA repair pathways. Ataxia-telangiectasia and Rad3-Related protein (ATR) plays a pivotal role in the recognition of DNA damage induced by chemotherapy and radiation and downstream activation of DDR pathways. Furthermore, a growing body of evidence indicates DNA damage and inhibition of ATR can stimulate a proinflammatory response that activates innate immunity against tumour cells. Here, we investigated the change of gene expression of treated glioblastoma cell lines from TMZ+RT and ATR inhibition (using gartisertib (M4344)) combined with TMZ+RT.
2024-01-18 | GSE211272 | 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
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
Project description:The PIKK superfamily member ATR is a key factor in DNA damage response (DDR) and is vital for the maintenance of genomic stability. DNA single strand breaks (SSBs) and replication stress activate ATR to phosphorylate a wide range of downstream substrates, which activates cell cycle checkpoint, senescence induction, cell death, and R-loop disintegration. ATR mutation causes the human ATR-Seckel syndrome, characterized by dwarfism, microcephaly and intellectual disabilities. Recent studies have implied ATR in non-nuclear functions; however, ATR's function in mitochondrial metabolism and a link to human diseases remains largely unknown. Here we show that ATR is located in mitochondria and its deletion alters mitochondrial dynamics prior to the DDR. ATR deletion disturbs the electron transfer chain (ETC) resulting in ROS overproduction and switches energy production from OXPHOS to the TCA cycle. Multi-omics analyses together with biochemical studies showed an imbalance of ETC proteins and membrane lipids accompanied with a dysregulation of key metabolic signaling pathways, including AMPK, mTOR and PGC1α. Pharmacological intervention of AMPK signaling or ETC functions delineates the metabolic pathways affected in ATR deleted cells. Mitochondrial metabolic dysfunction is more pronounced in ATR deleted neural cells and brain tissues, implicating a connection with neuropathological processes. Thus, ATR plays, beyond its well-known DDR function, an important role for cell metabolism and mitochondrial functionality, which contributes to the manifestation of neuronal deficit of ATR-Seckel.
2021-05-05 | PXD013414 | Pride