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Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7

ABSTRACT: Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7

PROVIDER: PRJEB62094 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR11435634.fastq.gz	Fastqsanger.gz
	ERR11435635.fastq.gz	Fastqsanger.gz
	ERR11435636.fastq.gz	Fastqsanger.gz
	ERR11435637.fastq.gz	Fastqsanger.gz
	ERR11435638.fastq.gz	Fastqsanger.gz

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Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7

Project description:Synthetic lethal CRISPR screen in MCF10A FBXW7 isogenic models

2023-05-22 | E-MTAB-12939 | biostudies-arrayexpress

Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC

Project description:The FBXW7 tumour suppressor is commonly mutated, deleted or hypermethylated in a variety of cancer histologies. The tumour suppressive role of the FBXW7 protein has been ascribed to its ability to drive the ubiquitination and degradation of oncoproteins via its role as a substrate recognition subunit of SCF complexes that mediate E3 ubiquitin ligation. Despite this molecular understanding, therapeutic approaches that target tumoural FBXW7 defects do not exist. To identify candidate vulnerabilities put in place by FBXW7 dysfunction, we carried out genome-wide CRISPR-Cas9 screens, focussed RNA interference screens and whole proteome mass spectrometry profiling in multiple FBXW7 wild type and defective isogenic cell systems. These identified candidate FBXW7 synthetic lethal effects, including those involving SCF-related proteins (e.g. CAND1), proteins involved in the response to replication fork stress (ATR, RAD9A and CHEK1) and also proteins involved in replication licencing such as CDC7 and its substrate GINS4. The ATR, CHEK1 and CDC7 synthetic lethal effects were confirmed using drug-like small molecule inhibitors. Integration of proteomic profiling data indicated that FBXW7 defective cells express elevated levels of the replication factor RIF1. Functional experiments showed that FBXW7 vs. CDC7 synthetic lethality is RIF1 dependent and explained by RIF1 being required for CDC7 inhibitor-induced replication fork stalling. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area.

2024-06-16 | PXD043904 | Pride

The role of CDC7 in Melanoma cancer growth and progression

Project description:Disruptor of Cell Division Cycle 7 (CDC7) expression is elevated in many cancer types including melanoma. Therefore, we analyzed the role of CDC7 in melanoma. Pharmacological inhibition of CDC7 expression in Melanoma cancer cell lines resulted in decreased proliferation, and increased cell death.

2022-08-10 | GSE158621 | GEO

Combinatorial Gene Essentiality and Pharmacological Profiling uncovers enhancer-mediated synthetic lethal interactions with Mediator Kinase

Project description:Combinatorial Gene Essentiality and Pharmacological Profiling uncovers enhancer-mediated synthetic lethal interactions with Mediator Kinase

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Combinatorial Gene Essentiality and Pharmacological Profiling uncovers enhancer-mediated synthetic lethal interactions with Mediator Kinase [ChIP]

Project description:Combinatorial Gene Essentiality and Pharmacological Profiling uncovers enhancer-mediated synthetic lethal interactions with Mediator Kinase [ChIP]

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FBXW7

Project description:FBXW7

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G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

Project description:Neurofibromatosis Type II is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent growth of benign tumors from Schwann cells, the glia of the peripheral nervous system. Unfortunately, no pharmacological therapy is currently available for NFII. Here, we undertake a genome-wide CRISPR/cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant cells but not NF2 wildtype cells. We thereby identify ACSL3 and G6PD as two synthetic-lethal partners for NF2. We find that NF2 mutant Schwann cells are vulnerable to G6PD inhibition because they have low levels of ME1. G6PD and ME1 redundantly generate cytosolic NADPH needed by cells to fight oxidative stress. Lack of either one of the two is compatible with cell viability, but down-regulation of both leads to Schwann cell death. Since genetic deficiency for G6PD is tolerated in the human population, this raises the possibility that G6PD could be a pharmacological target for NFII.

2024-04-24 | GSE219136 | GEO

G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

2024-04-24 | GSE219135 | GEO

Combinatorial Gene Essentiality and Pharmacological Profiling uncovers enhancer-mediated synthetic lethal interactions with Mediator Kinase [RNA-Seq]

Project description:Combinatorial Gene Essentiality and Pharmacological Profiling uncovers enhancer-mediated synthetic lethal interactions with Mediator Kinase [RNA-Seq]

| PRJNA687682 | ENA

Inactivation of CDK2 is synthetic lethal to MYCN-overexpressing cancer cells

Project description:Two genes have a synthetic lethal relationship when silencing or inhibition of one gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetic lethal to neuroblastoma cells with MYCN amplification and overexpression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by three RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53 and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with Roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetic lethal relation between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. CDK2 shRNA in a tet repressor system was stably transfected in the IMR32 cell line. Time course analysis was performed in triplicate after induction of CDK2 shRNA at 5 time points.

2014-05-19 | E-GEOD-16480 | biostudies-arrayexpress

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