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Transcription profiling of rat Schwann cells in response to NF1 RNAi treatment and the MEK inhibitor U0126

ABSTRACT: Comparison of the changes in the gene expression profile of cells in which NF1 has been knocked down by RNAi in the presence/absence of the MEK inhibitor UO126 Experiment Overall Design: Primary Rat Schwann cells were transiently transfected with either scrambled (control) or NF1 RNAi oligonucleotides in the presence/absence of the MEK inhibitor UO126. Total RNA was then harvested 48 hours post-transfection. Three independent biological replicates were analysed.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Luke Adam Noon

PROVIDER: E-GEOD-10376 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression profiling of mammalian Schwann cells in response to NF1 RNAi treatment and the MEK inhibitor U0126

Project description:Comparison of the changes in the gene expression profile of cells in which NF1 has been knocked down by RNAi in the presence/absence of the MEK inhibitor UO126 Keywords: RNAi knock-down of NF1 gene

2008-02-08 | GSE10376 | GEO

Intrinsic Resistance to MEK Inhibition Through BET Protein Mediated Kinome

Project description:Mutation or deletion of Neurofibromin (NF1), an inhibitor of RAS signaling, frequently occurs in epithelial ovarian cancer (EOC), supporting therapies that target downstream RAS effectors, such as the RAF-MEK-ERK pathway. However, no comprehensive studies have been carried out testing the efficacy of MEK inhibition in NF1-deficient EOC. Here, we performed a detailed characterization of MEK inhibition in NF1-deficient EOC cell lines using kinome profiling and RNA sequencing. Our studies showed MEK inhibitors were ineffective at providing durable growth inhibition in NF1-deficient cells due to kinome reprogramming. MEKi-mediated destabilization of FOSL1 resulted in induced expression of RTKs and their downstream RAF and PI3K signaling overcoming MEKi therapy. MEKi synthetic enhancement screens identified BRD2 and BRD4 as integral mediators of the MEKi-induced RTK signatures. Inhibition of BET proteins using BET bromodomain inhibitors (BETi) blocked MEKi-induced RTK reprogramming, indicating BRD2 and BRD4 represent promising therapeutic targets in combination with MEKi to block resistance due to kinome reprogramming in NF1-deficient EOC.

2019-05-17 | GSE127886 | GEO

Expression data of three sets of cells: (1) Schwann cells and macrophages from 1m-old WT DRG, (2) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 1m-old neurofibroma, (3) Schwann cells (Nf1-/-) and macrophages (Nf1+/+) from 7m-old neurofibroma

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2017-05-01 | E-GEOD-78901 | biostudies-arrayexpress

Genome-wide gene expression analysis of neurofibroma-derived NF1+/- and NF1-/- Schwann cells

Project description:Analysis of the effect of NF1 second hit mutation to the reading of the whole human genome by comparing the gene expression profiles of neurofibroma derived Schwann cell cultures representing two different NF1 genotypes (NF1+/- and NF1-/-).

2016-12-22 | GSE32029 | GEO

Dual inhibition of SHP2 and autophagy suppresses NF1-associated malignant peripheral nerve sheath tumors

Project description:Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of premature death for patients with Neurofibromatosis type 1 and no approved targeted therapies are available. Benign plexiform neurofibromas have been successfully treated with selumetinib, a MEK inhibitor, but after progression to MPNST, MEK inhibition alone is not effective. Frequently, adaptive responses to single agent targeted inhibitors invokes alterations in receptor tyrosine kinase expression and feedback regulation that leads to inhibitor bypass. Here, the effects of SHP099, an inhibitor of the protein-tyrosine phosphatase SHP2 (encoded by the PTPN11 gene) was tested alone and in combination with trametinib (MEKi) in an orthotopic implantation murine model of NF1 MPNST with defined gentotype (NI, Nf1-/-;Ink4a/Arf-/-). Kinase enrichment proteomic analysis was performed using tumor tissue from vehicle, SHP099, or trametinib and SHP099 in combination for 5, 15, or 28 days to evaluate the effects on the functional kinome.

2024-11-20 | PXD035998 | Pride

Dual inhibition of SHP2 and autophagy suppresses NF1-associated malignant peripheral nerve sheath tumors

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2024-11-20 | PXD035999 | Pride

Selumetinib in adults with NF1 and inoperable plexiform neurofibroma

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2024-10-07 | GSE277520 | GEO

MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors, despite transcriptional feedback onto ERK.

Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials.

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Transcription profiling of mouse chondrocytes treated with MEK/ERK pathway inhibitors

Project description:Objectives: To identify similarities and differences in gene expression data in the MEK/ERK and PI3K pathways and to determine how histone modification affects these same pathways. Goal: To identify and functionally characterize novel targets of these signaling pathways in the context of chondrocyte differentiation. Experiment Overall Design: Cartilage derived from the hind limbs of CD1 mice staged at 15.5 days of embryonic development were dissected and plated in primary chondrocyte monolayer cultures. Cells were treated with MEK/ERK pathway inhibitors (SB202190 and UO126), a PI3K inhibitor (LY294002), a histone deacetylase inhibitor (Trichostatin A) and the vehicle control (DMSO) for 24 hours. Total RNA was isolated from these samples and hybridized to Affymetrix MOE 430 2.0 chips at the London Regional Genomics facility. Experiment Overall Design: A total of 15 genechips were analyzed between 4 treatments and the vehicle (DMSO) control. Three biological replicates per treatment were executed. Experiment Overall Design: Experiment Overall Design:

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