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Mechanistic study of Wee1 kinase inhibition with AZD1775 exposes drug targetable vulnerabilities in acute B-lymphoblastic leukemia [GROseq]

ABSTRACT: Nascent transcription and enhancer activity was studied using GRO-seq in the acute lymphoblastic leukemia cell line RS4;11 upon inhibition of the WEE1 kinase.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220099 | GEO | 2023/05/14

REPOSITORIES: GEO

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Mechanistic study of Wee1 kinase inhibition with AZD1775 exposes drug targetable vulnerabilities in acute B-lymphoblastic leukemia [scMultiome]

Project description:This study characterized the effect of WEE1 kinase inhibition using AZD1775 treatment on single-cell accessible chromatin and gene expression profile using the 10x Genomics multiome protocol (ATAC + Gene Expression Assay) in the acute lymphoblastic leukemia cell line RS4;11 that represents the KMT2A-rearranged subtype.

2023-05-14 | GSE220112 | GEO

Mechanistic study of Wee1 kinase inhibition with AZD1775 exposes drug targetable vulnerabilities in acute B-lymphoblastic leukemia [scATAC-seq]

Project description:This study characterized the effect of WEE1 kinase inhibition using AZD1775 treatment on single-cell accessible chromatin and gene expression profile in the acute lymphoblastic leukemia cell line RS4;11 that represents the KMT2A-rearranged subtype.

2023-05-14 | GSE218805 | GEO

Mechanistic study of Wee1 kinase inhibition with AZD1775 exposes drug targetable vulnerabilities in acute B-lymphoblastic leukemia [scRNA-seq]

Project description:This study characterized the effect of WEE1 kinase inhibition using AZD1775 treatment on single-cell gene expression profile using the 10x Genomics protocol in the acute lymphoblastic leukemia cell lines RS4;11 (KMT2A-rearranged subtype) and Nalm6 (other subtype).

2023-05-14 | GSE218621 | GEO

Mechanistic study of Wee1 kinase inhibition with AZD1775 exposes drug targetable vulnerabilities in acute B-lymphoblastic leukemia [scRNA-seq PDX MLL-7]

2023-05-14 | GSE220476 | GEO

Mechanistic study of Wee1 kinase inhibition with AZD1775 exposes drug targetable vulnerabilities in acute B-lymphoblastic leukemia

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-05-14 | GSE220114 | GEO

Wee1 inhibition in acute lymphoblastic leukemia with MLL rearrangement.

Project description:Enhancer activity and RUNX1 binding was studied using ChIP-seq in mixed lineage leukemia t(4;11) rearranged acute lymphoblastic leukemia upon inhibition of the WEE1 kinase.

2020-10-30 | GSE148195 | GEO

Identifying and overcoming a mechanism of resistance to Wee1 kinase inhibitor AZD1775 in high grade serous ovarian cancer cells (OVCAR8)

Project description:Treatment of Human high grade serous ovarian cancer cell line, OVCAR8, with WEE1 kinase inhibitor AZD1775

2020-12-01 | GSE141990 | GEO

Identifying and overcoming a mechanism of resistance to Wee1 kinase inhibitor AZD1775 in high grade serous ovarian cancer cells (ES-2)

Project description:Treatment of Human high grade serous ovarian cancer cell line, ES-2, with WEE1 kinase inhibitor AZD1775

2020-12-01 | GSE142124 | GEO

TRRAP-mediated regulation of Wee1

Project description:The G2 DNA damage checkpoint inhibits Cdc2 and mitotic entry through the dual regulation of Wee1 and Cdc25 by the Chk1 effector kinase. Up-regulation of Chk1 by mutation or overexpression bypasses the requirement for up-stream regulators or DNA damage to promote a G2 cell cycle arrest. We screened in fission yeast for mutations that rendered cells resistant to overexpressed Chk1. We identified a mutation in tra1, which encodes one of two homologs of TRRAP, an ATM/R-related pseudokinase that scaffolds several histone acetyltransferase (HAT) complexes. Inhibition of histone deacetylases reverts the resistance to overexpressed Chk1, suggesting this phenotype is due to a HAT activity, though expression of checkpoint and cell cycle genes is not greatly affected. Cells with mutant or deleted tra1 activate Chk1 normally and are checkpoint proficient. However, these cells are semi-wee even when overexpressing Chk1, and accumulate inactive Wee1 protein. The Cdr (changed division response) kinases Cdr1 and Cdr2 are negative regulators of Wee1, and while best characterized in the cellular response to limited nutrition, we show that they are required for the Tra1-dependent alterations to Wee1 function. This identifies Tra1 as another component controlling the timing of entry into mitosis via Cdc2 activation. Two and three independent microaaray experiments were done for wild type and the mutant (tra1-1) respectively.

2010-04-11 | E-GEOD-12674 | biostudies-arrayexpress

Heterogeneity of Myc expression in breast cancer exposes pharmacological vulnerabilities revealed through executable mechanistic modeling.

Project description:Cells with higher levels of Myc proliferate more rapidly and supercompetitively eliminate neighboring cells. Nonetheless, tumor cells in aggressive breast cancers typically exhibit significant and stable heterogeneity in their Myc levels, which correlates with refractoriness to therapy and poor prognosis. This suggests that Myc heterogeneity confers some selective advantage on breast tumor growth and progression. To investigate this, we created a traceable MMTV-Wnt1-driven in vivo chimeric mammary tumor model comprising an admixture of low-Myc- and reversibly switchable high-Myc-expressing clones. We show that such tumors exhibit interclonal mutualism wherein cells with high-Myc expression facilitate tumor growth by promoting protumorigenic stroma yet concomitantly suppress Wnt expression, which renders them dependent for survival on paracrine Wnt provided by low-Myc-expressing clones. To identify any therapeutic vulnerabilities arising from such interdependency, we modeled Myc/Ras/p53/Wnt signaling cross talk as an executable network for low-Myc, for high-Myc clones, and for the 2 together. This executable mechanistic model replicated the observed interdependence of high-Myc and low-Myc clones and predicted a pharmacological vulnerability to coinhibition of COX2 and MEK. This was confirmed experimentally. Our study illustrates the power of executable models in elucidating mechanisms driving tumor heterogeneity and offers an innovative strategy for identifying combination therapies tailored to the oligoclonal landscape of heterogenous tumors.

| S-EPMC6825310 | biostudies-literature

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