Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The hippo pathway effector protein YAP modulated resistance to trametinib neuroblastomas with hyperactivated RAS pathway signalling

ABSTRACT: The hippo pathway effector protein YAP modulated resistance to trametinib neuroblastomas with hyperactivated RAS pathway signalling

PROVIDER: PRJNA540060 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR8980740_1.fastq.gz	Fastqsanger.gz
	SRR8980740_2.fastq.gz	Fastqsanger.gz
	SRR8980750_1.fastq.gz	Fastqsanger.gz
	SRR8980750_2.fastq.gz	Fastqsanger.gz
	SRR8980731_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 42

Similar Datasets

The hippo pathway effector protein YAP modulated resistance to trametinib neuroblastomas with hyperactivated RAS pathway signalling

Project description:We sequenced seven neuroblastoma cell lines, including the parental NLF neuroblastoma cell line and three modified NLF cell lines.

2019-10-26 | GSE130401 | GEO

Modelling HNSCC in mice with hyperactivated NRF2 pathway

Project description:Modelling HNSCC in mice with hyperactivated NRF2 pathway

| PRJNA1287799 | ENA

Differentation in neuroblastomas

Project description:Expression profiling according to differentiation was analysed in 34 neuroblastomas

2009-02-20 | GSE14880 | GEO

YAP1 Mediates Resistance to MEK1/2 Inhibition in Neuroblastomas with Hyperactivated RAS Signaling.

Project description:Relapsed neuroblastomas are enriched with activating mutations of the RAS-MAPK signaling pathway. The MEK1/2 inhibitor trametinib delays tumor growth but does not sustain regression in neuroblastoma preclinical models. Recent studies have implicated the Hippo pathway transcriptional coactivator protein YAP1 as an additional driver of relapsed neuroblastomas, as well as a mediator of trametinib resistance in other cancers. Here, we used a highly annotated set of high-risk neuroblastoma cellular models to modulate YAP1 expression and RAS pathway activation to test whether increased YAP1 transcriptional activity is a mechanism of MEK1/2 inhibition resistance in RAS-driven neuroblastomas. In NLF (biallelic NF1 inactivation) and SK-N-AS (NRAS Q61K) cell lines, trametinib caused a near-complete translocation of YAP1 protein into the nucleus. YAP1 depletion sensitized neuroblastoma cells to trametinib, while overexpression of constitutively active YAP1 protein induced trametinib resistance. Mechanistically, significant enhancement of G1-S cell-cycle arrest, mediated by depletion of MYC/MYCN and E2F transcriptional output, sensitized RAS-driven neuroblastomas to trametinib following YAP1 deletion. These findings underscore the importance of YAP activity in response to trametinib in RAS-driven neuroblastomas, as well as the potential for targeting YAP in a trametinib combination. SIGNIFICANCE: High-risk neuroblastomas with hyperactivated RAS signaling escape the selective pressure of MEK inhibition via YAP1-mediated transcriptional reprogramming and may be sensitive to combination therapies targeting both YAP1 and MEK.

| S-EPMC6911631 | biostudies-literature

Capicua-dependent transcriptional changes in human cancer cell lines treated with trametinib

Project description:We performed a genome-scale CRISPR screen in a KRAS-mutant pancreatic cancer cell line treated with the MEK inhibitor trametinib, and found that loss of the transcriptional repressor CIC confers resistance to MEK inhibition. We determined that CIC loss also confers resistance to MEK or BRAF inhibition in lung cancer, colorectal cancer, and melanoma cell lines with mutant RAS or BRAF. CIC is a transcriptional repressor that is phosphorylated and inhibited by the MAPK pathway. We hypothesized that inhibition of the MAPK pathway would lead to activation of CIC and repression of CIC target genes. Loss of CIC would therefore restore expression of these genes, conferring drug resistance. To identify the relevant CIC target genes that mediate trametinib resistace, we generated 4 Cas9-expressing cell lines from different lineages and with different RAS or RAF mutations, and generated control (gGFP) or CIC-knockout (gCIC) cell lines. We treated cells with DMSO or trametinib for 24 hours, and performed NRA-seq. We found that trametinib treatment reduces expression of at least one member of the PEA3 family of ETS transcription factors (ETV1, ETV4, and ETV5) in all cell lines assessed, and that loss of CIC results in maintained expression of these genes despite MEK inhibition. We further validated that ETV1, 4, and 5 expression was necessary for resistance mediated by CIC loss; and that ETV1, 4, or 5 expression was sufficient to confer trametinib resistance.

2017-05-31 | GSE78519 | GEO

DNA methylation data from 58 primary neuroblastomas

Project description:Genome wide DNA methylation profiling of primary neuroblastomas. The Illumina 450k methylation array was used to obtain DNA methylation profiles across approximately 485,000 CpGs in 58 neuroblastomas. Data were analyzed with regard to differential methylation at ATRX and DAXX loci in relation to genomic MYCN, TERT and ATRX status, presence of alternative lengthening of telomeres (ALT) and TERT expression. The analysis is part of the study: A mechanistic classification of clinical phenotypes in neuroblastoma (Ackermann et al., 2018)

2018-12-19 | GSE120650 | GEO

The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan

Project description:Suppression of the insulin-IGF-mTORC1-Ras network ameliorates aging in animals. Many drugs have targets in the network because of its roles in cancer and metabolic disease and are candidates for repurposing as geroprotectors. Rapamycin, an established geroprotective drug, blocks mTORC1 signaling, and trametinib inhibits the Ras-MEK-ERK pathway. In this study, we assessed survival and health of male and female mice treated with trametinib, rapamycin or their combination. We show here that trametinib treatment extended lifespan in both sexes and that its combination with rapamycin was additive. Combination treatment reduced liver tumors in both sexes and spleen tumors in male mice, blocked the age-related increase in brain glucose uptake and strongly reduced inflammation in brain, kidney, spleen and muscle and circulating levels of pro-inflammatory cytokines. We conclude that trametinib is a geroprotector in mice and that its combination with rapamycin is more effective than either drug alone, making the combination a candidate for repurposing as a gerotherapy in humans.

2025-03-27 | GSE288795 | GEO

HDAC3 is critical in tumor development and therapeutic resistance in Kras-mutant non-small cell lung cancer [RNA-seq trametinib entinostat treatment]

Project description:HDAC3 is one of the main targets of Histone Deacetylase (HDAC) inhibitors in clinical development as cancer therapies, yet the in vivo role of HDAC3 in solid tumors is unknown. Here, we identified a critical role for HDAC3 in KRAS mutant lung cancer. Using genetic engineered mouse models (GEMM), we found that HDAC3 is required for lung tumor growth in vivo. HDAC3 was found to direct and enhance the transcription effects of the lung cancer lineage transcription factor NKX2-1 to mediate expression of a common set of target genes. We identified FGFR1 as a critical new target of HDAC3. Leveraging this, we identified that an HDAC3-dependent transcriptional cassette becomes hyperactivated as KRAS/LKB1 mutant cells develop resistance to the MEK inhibitor trametinib, and this can be reversed by treatment with the HDAC1/HDAC3 inhibitor entinostat. We found that the combination of entinostat plus trametinib treatment elicits therapeutic benefit in the KRAS/LKB1 GEMM.

2023-07-14 | GSE164757 | GEO

Trametinib sensitizes KRAS-mutant lung adenocarcinoma tumors to PD-1/PD-L1 axis blockade via Id1 downregulation

Project description:The identification of novel therapeutic strategies to overcome the intrinsic or acquired resistance to trametinib in mutant KRAS lung adenocarcinoma (LUAD) is a major challenge. This study analyzes the effects of trametinib in Id1, a key factor involved in the oncogenic KRAS pathway, and investigates the Id1 role in acquire resistance and synergy with immunotherapy in KRAS-driven LUAD. Restoring the antitumor immune response by blocking programmed-cell death protein 1 (PD-1) and programmed-cell death-ligand 1 (PD-L1) pathway represents a major breakthrough in non-small-cell lung cancer (NSCLC) treatment. Nevertheless, a high proportion of LUAD patients with KRAS alterations remain refractory to this therapy. Material and Methods: To explore whether MEK1/2 inhibition reduces Id1 expression, in vitro and in vivo experiments were conducted in KRAS-mutant NSCLC cells and murine models. RNAseq analysis was performed to elucidate the pathways involved in Id1 inhibition. Apoptosis and PD-L1 expression was measured by flow cytometry. Synergy of trametinib combined with anti-PD1 was investigated in KRAS-mutant LUAD mouse models. Results: Using preclinical syngeneic KRAS-mutant lung cancer mouse models, we demonstrate that trametinib synergizes with PD-1 blockade to reduce lung cancer progression and increase mice overall survival. This antitumor activity was linked to the degradation of Id1 via proteasome, and an enhanced INF-Y-mediated PD-L1 tumor cell expression in KRAS-mutant tumor cells. This effect required CD8+ T cells, boosted the intratumoral CD8+/Treg ratio, reducing the intratumoral Treg/CD4+ ratio. Conclusions: Our data may support the role of Id1 in the trametinib antitumoral effect, sustaining the mitogen-activated protein kinases (MAPK) signaling pathway involved in the trametinib acquired resistance cells and sensitizing KRAS-mutant lung tumors to PD-1 inhibitors, through PD-L1 overexpression.

2024-05-17 | GSE236258 | GEO

Proteogenomic characterization of developmental defects in the forebrain resulting from hyperactivated mTOR signaling

Project description:Hyperactivated mTOR signaling in the developing brain by mutation of TSC1 genes has multiple forms of pathology including tuberous sclerosis complex (TSC). To examine the downstream networks affected in the developing brain by hyperactivated mTOR signaling, we performed an integrated analysis of transcriptomic and proteomic analysis of forebrain of wild-type and TSC1/Emx1-Cre mouse. Our results provide novel and fundamental molecular bases for understanding hyperactivaed mTOR signaling-induced brain defects which can in turn facilitate identification of potential diagnostic markers and therapeutic targets for mTOR signaling-related neurological disorders.

2018-08-16 | PXD005768 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data