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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218805 | 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 [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 [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 [GROseq]

Project description: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.

2023-05-14 | GSE220099 | 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

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

The effect of WEE1 inhibition on the replication timing program

Project description:As a part of the project looking into the role of WEE1 in regulating replication initiation, we report the replication timing analysis of the U2OS cells treated with WEE1 kinase inhibitor AZD1775

2019-12-09 | GSE138998 | GEO

Development and Characterization of a Wee1 Kinase Degrader

Project description:The G1/S cell-cycle checkpoint is frequently dysregulated in cancer, leaving cancer cells particularly reliant on a functional G2/M checkpoint to prevent excessive DNA damage. Inhibiting regulators of the G2/M checkpoint can therefore drive cancer cells into premature mitosis, ultimately causing cell death by mitotic catastrophe. One such regulator is Wee1, a nuclear tyrosine kinase that delays mitotic entry by phosphorylating CDK1 at Tyr15. Previous drug development efforts targeting Wee1 resulted in the clinical-grade inhibitor, AZD1775. However, AZD1775 is burdened by dose- limiting adverse events, and has off-target PLK1 activity. In an attempt to overcome these limitations, we designed small molecule degraders of Wee1 by conjugating AZD1775 to the cereblon (CRBN)- binding ligand, pomalidomide, as informed by molecular docking. The resulting lead compound, ZNL- 02-096, degrades Wee1 while sparing PLK1, induces G2/M phase accumulation at up to 10-fold lower concentrations than AZD1775, and potently synergizes with Olaparib in ovarian cancer cell lines. We demonstrate that ZNL-02-096 has CRBN-dependent pharmacology that is distinct from the conventional catalytic inhibitor, AZD1775, which justifies further evaluation of selective Wee1 degraders.

2019-11-18 | PXD015513 | Pride

Increased HDAC Activity and c-MYC Expression Mediate Acquired Resistance to WEE1 Inhibition in Acute Leukemia

Project description:WEE1 is a cell cycle and DNA damage response kinase that is emerging as a therapeutic target for cancer. AZD1775 is a small molecule inhibitor of WEE1, currently in early phase clinical trials as a single agent and in combination with more conventional anti-neoplastic agents. As resistance to kinase inhibitors is frequent, we sought to identify mechanisms of resistance to WEE1 inhibition in acute leukemia. We found that AZD1775 resistant cell lines are dependent upon increased HDAC activity for their survival, in part due to increased KDM5A activity. In addition, gene expression analyses demonstrate HDAC dependent increase in MYC expression and c-MYC activity in AZD1775 treated resistant cells. Overexpression of c-MYC confers resistance to AZD1775 in cell lines with low base line expression. Pharmacologic inhibition of BRD4, and thereby c-MYC, partially abrogated resistance to AZD1775. Thus, acquired resistance to WEE1 inhibition may be reversed by HDAC or BRD4 inhibition in leukemia cells.

2020-02-25 | GSE145129 | GEO

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