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Consensus Molecular Subtype predicts differential vulnerability of colorectal cancer to the survivin suppressant YM155 II

ABSTRACT: Consensus Molecular Subtype predicts differential vulnerability of colorectal cancer to the survivin suppressant YM155 II

PROVIDER: PRJNA478932 | ENA |

REPOSITORIES: ENA

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Consensus Molecular Subtype predicts differential vulnerability of colorectal cancer to the survivin suppressant YM155 I

Project description:Tumor heterogeneity is a major challenge to the treatment of colorectal cancer (CRC). Recently, a transcriptome-based classification was developed, segregating CRC into four consensus molecular subtypes (CMS) with distinct biological and clinical characteristics. Here, we applied the CMS classification on CRC cell lines to identify novel subtype-specific drug vulnerabilities. We combined publicly available transcriptome data from multiple resources to assign 159 CRC cell lines to CMS. By integrating results from large scale drug screens, we discovered that CMS1 cancer is highly vulnerable to the survivin suppressor YM155. We confirmed our results using an independent panel of CRC cell lines and demonstrate a 100-fold higher sensitivity of CMS1 lines. This vulnerability was specific to YM155 and not observed for commonly used chemotherapeutic agents. In CMS1 cancer, low concentrations of YM155 induced apoptosis and expression signatures associated with NFkappaB and ER stress mediated apoptosis signaling. Using a genome-wide CRISPR/Cas9 screen, we discovered a novel role of genes involved in LDL-receptor recycling as modulators of YM155 response in CMS1 CRC. Our work shows that combining drug response data with CMS classification in cell lines can reveal specific vulnerabilities and propose YM155 as novel CMS1 specific drug.

2018-07-03 | GSE116529 | GEO

Consensus Molecular Subtype predicts differential vulnerability of colorectal cancer to the survivin suppressant YM155 II

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Consensus Molecular Subtype predicts differential vulnerability of colorectal cancer to the survivin suppressant YM155 I

Project description:Consensus Molecular Subtype predicts differential vulnerability of colorectal cancer to the survivin suppressant YM155 I

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Drug-induced mitochondrial oxidative stress is responsible for various effects of the survivin inhibitor Sepantronium Bromide (YM155) in triple negative breast cancer cells

Project description:Sepantronium bromide (YM155), a transcriptional inhibitor of anti-apoptotic protein survivin, is considered as a potential drug candidate for triple negative breast cancers (TNBC). Regardless of its excellent performance in pre-clinical models of TNBC, in patients, this drug was unable to outperform the standard chemotherapy docetaxel. The goal of this study was to identify the pathways/molecules affected by YM155 in TNBC cell lines. Detailed biochemical analysis of the paired YM155-sensitive and resistant cell lines indicates that induction of mitochondrial oxidative stress is a first-line response to the drug, ultimately leading to growth inhibition and induction of cell death. Multiple pathways involved in dampening oxidative stress-induced damages are differentially regulated in YM155-resistant cells. Furthermore, the emergence of YM155 resistance is associated with an extensive transcriptional reprogramming and alteration of many more biological pathways in addition to those identified by biochemical assays. Molecules associated with these biological pathways will potentially serve as biomarkers predicting YM155 sensitivity in TNBC cells.

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Project description:CD4 T cells from 4 healthy women were activated with aCD3 and treated with the survivin inhibitor YM155, 10 ng/ml or control during 24 hours. The last 2 hours with upplement of IFNg. The objective was to understand the action of survivin (coded by BIRC5 gene) in CD4 T cells.

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Project description:CD4 T cells from 4 healthy women were activated with aCD3 and treated with the survivin inhibitor YM155, 10 ng/ml or control during 72 hours. The last 2 hours with upplement of IFNg. The objective was to understand the action of survivin (coded by BIRC5 gene) in CD4 T cells.

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YM155 treated KYSE410

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Project description:Multi-omics integration identifies a selective vulnerability of colorectal cancer molecular subtypes to YM155

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Survivin ChIPseq

Project description:ChIPseq analysis of survivin chromatin binding in activated CD4+ T cells

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