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

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

PROVIDER: PRJNA606086 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11069663.fastq.gz	Fastqsanger.gz
	SRR11069664.fastq.gz	Fastqsanger.gz
	SRR11069665.fastq.gz	Fastqsanger.gz
	SRR11069666.fastq.gz	Fastqsanger.gz
	SRR11069667.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

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 baseline 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.

| S-EPMC7066074 | biostudies-literature

Acquired MEN1 mutations mediate resistance to Menin inhibition.

Project description:Acquired MEN1 mutations mediate resistance to Menin inhibition.

| PRJNA803137 | ENA

Cell cycle-dependent YTHDF2 promotes mitotic entry by repressing WEE1

Project description:The m6A modification regulates mRNA stability and translation. Here we show that transcriptomic m6A modification is dynamic and the m6A reader protein YTHDF2 promotes mRNA decay during the cell cycle. Depletion of YTHDF2 leads to the delay of mitotic entry due to overaccumulation of WEE1, a negative regulator of CDK1. We demonstrate that WEE1 transcripts contain m6A modification, which promotes their decay through the m6A reader YTHDF2. Moreover, we found that YTHDF2 protein stability is dependent on CDK1 activity. Thus, CDK1, YTHDF2, and WEE1 form a feedforward regulatory loop to promote mitotic entry. We further identified CUL1, CUL4A, DDB1, and SKP2 as components of E3 ubiquitin ligase complexes that mediate YTHDF2 proteolysis. Our study provides insights into how cell cycle mediators modulate transcriptomic m6A modification, which in turn regulates the cell cycle.

2020-01-01 | GSE134700 | GEO

GCN2 is a determinant of the response to WEE1 kinase inhibition in small-cell lung cancer

Project description:Patients with small-cell lung cancer (SCLC) are in dire need of more effective therapeutic options. Frequent disruption of the G1 checkpoint in SCLC cells creates a greater dependency of these cells on the G2/M checkpoint to maintain genomic integrity. Indeed, in pre-clinical models, inhibiting the G2/M kinase WEE1 shows promise in inhibiting SCLC growth. However, toxicity and acquired resistance limit the clinical effectiveness of this strategy. Here we conducted CRISPR/Cas9 knockout screens to identify genes influencing the response of SCLC cells to WEE1 kinase inhibition. These screens uncovered a role for the GCN2 amino acid-sensing pathway in modulating the response of SCLC cells to WEE1 inhibition. Rapid activation of GCN2 upon WEE1 inhibition triggers a stress response. Pharmacological activation of the GCN2 pathway synergizes with WEE1 inhibition. Thus, activation of the GCN2 amino acid-sensing pathway represents a novel approach for augmenting the efficacy of WEE1 inhibitors in SCLC.

2024-07-16 | GSE246354 | GEO

Extracellular pyridine nucleotides mediate systemic acquired resistance in Arabidopsis thaliana

Project description:Extracellular pyridine nucleotides mediate systemic acquired resistance in Arabidopsis thaliana

| PRJNA933934 | ENA

Acquired MEN1 mutations mediate resistance to Menin inhibition [RNA-seq]

Project description:Acquired MEN1 mutations mediate resistance to Menin inhibition [RNA-seq]

| PRJNA803146 | ENA

Acquired MEN1 mutations mediate resistance to Menin inhibition [CHIP-seq]

Project description:Acquired MEN1 mutations mediate resistance to Menin inhibition [CHIP-seq]

| PRJNA803145 | ENA

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

Synthetic lethal screen reveals selective vulnerability of ATRX-mutant cancers to WEE1 inhibition

Project description:we performed a genome-wide synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for ATRX-mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase WEE1, uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines in vitro, as well as xenografts in vivo. The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring ATRX mutations, indicating that the synthetic lethal relationship between WEE1 and ATRX could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in ATRX.

2019-10-23 | GSE114035 | GEO

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