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Expression profiling of V600E BRAF and RTK-activated cells upon MEK inhibition

ABSTRACT: This study used microarray expression analysis to identify global changes in transcript alteration in response to MEK inhibition. Genes under ERK control were identified in a panel of V600E BRAF and RTK-activated tumor cells and xenografts, using short-term inhibition of ERK activity using the MEK inhibitor PD0325901 (Pfizer). This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE10086 | GEO | 2009/02/11

SECONDARY ACCESSION(S): PRJNA108653

REPOSITORIES: GEO

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Transcription profiling of human panel of V600E BRAF and RTK-activated tumor cells and xenografts upon MEK inhibition

Project description:This study used microarray expression analysis to identify global changes in transcript alteration in response to MEK inhibition. Genes under ERK control were identified in a panel of V600E BRAF and RTK-activated tumor cells and xenografts, using short-term inhibition of ERK activity using the MEK inhibitor PD0325901 (Pfizer). Experiment Overall Design: Cell lines growing in culture (n=12) and murine xenografts (n=2) were treated with the MEK inhibitor PD0325901 or vehicle alone as control. Paired analysis of MEK inhibited to control samples was performed for two groups of tumor cells, V600E BRAF and RTK. Time course analysis was performed on one representative cell line in order to first determine the optimal time point to detect changes in all cell lines.

2009-02-20 | E-GEOD-10086 | biostudies-arrayexpress

Transcription profiling of human cell lines in culture (n=12) and murine xenografts (n=2) were treated with the MEK inhibitor PD0325901 or vehicle alone as controlPaired MEK inhibited and control

2009-02-21 | E-GEOD-10087 | biostudies-arrayexpress

Paired MEK inhibited and control

2009-02-11 | GSE10087 | GEO

Transcription profiling of human SkMel-28 cells growing in culture treated with the MEK inhibitor PD0325901 for 2, 8, or 24 hours time course of MEK inhibition

Project description:This study used microarray expression analysis to identify global changes in transcript alteration in response to MEK inhibition. Genes under ERK control were identified in a representative V600E BRAF cell line as a function of time following exposure to a small molecule inhibitor of MEK. Experiment Overall Design: SkMel-28 cells growing in culture were treated with the MEK inhibitor PD0325901 for 2, 8, or 24 hours. Changes in RNA compared to reference (time =0) were measured using microarray analysis.

2009-02-21 | E-GEOD-10088 | biostudies-arrayexpress

Time course of MEK inhibition

Project description:This study used microarray expression analysis to identify global changes in transcript alteration in response to MEK inhibition. Genes under ERK control were identified in a representative V600E BRAF cell line as a function of time following exposure to a small molecule inhibitor of MEK. Keywords: Time course

2009-02-11 | GSE10088 | GEO

Reduced mTORC1 activity is associated with responsiveness to MEK inhibition (PD0325901) in gastric cancer cells.

Project description:Since gastric cancer (GC) is characterized by amplifications of receptor tyrosine kinases (RTK) and KRAS, targeting the RTK/KRAS downstream pathways could contribute to broader applicability of molecular targeted therapy in GC. Here, we assembled a panel of 49 GC cell lines and screened predictors for responsiveness to RAF/MEK/ERK pathway inhibition by comparing their sensitivity to MEK inhibition with alteration status of RTK/KRAS and phosphorylation status of RTK/KRAS downstream molecules. We found that GC cells with MET amplification or KRAS mutation tend to be sensitive to MEK inhibition. Furthermore, lower phosphorylation levels of mTORC1 targets, p70S6K and 4EBP1, was also significantly associated with sensitivity to MEK inhibition. Interestingly, the sensitive cells showed reduced mTORC1 activity accompanied by decreased rate of protein synthesis after MEK inhibition, suggesting that antiproliferative effect of MEK inhibition may be exerted through inhibition of protein synthesis, which was caused by reduced mTORC1 activity. Mechanistically, expression of some mTORC1 negative regulators, such as DDIT4, FOXO3, SESN1 and TSC1, were induced by MEK inhibition in highly-sensitive cell lines and knockdown of these negative regulators partially alleviated the suppression of mTORC1 activity and antiproliferative effect of MEK inhibition. Our data suggest that a subset of GCs, which would be distinguishable according to the predictive markers we identified, may be sensitive to MEK inhibition and have implications for the strategy in clinical trial of MEK inhibitors for GC.

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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.

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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.

2012-12-28 | GSE41747 | GEO

Transcriptional responses to GSK3 inhibitor and MEK inhibitor on 2i-adapted mouse embryonic stem cells

Project description:The objective of this study was to investigate the roles of GSK3 inhibitor CHIR99021 and MEK inhibitor PD0325901 on 2i-adapted mouse embryonic stem cells (ESCs) in serum-free conditions.Canonical Wnt signaling supports the pluripotency of mouse ESCs but also promotes differentiation of early mammalian cell lineages. To explain these paradoxical observations, we explored the gene regulatory networks at play. Canonical Wnt signaling is intertwined with the pluripotency network comprising Nanog, Oct4, and Sox2 in mouse ESCs. In defined media supporting the derivation and propagation of mouse ESCs, Tcf3 and β-catenin interact with Oct4; Tcf3 binds to Sox motif within Oct-Sox composite motifs that are also bound by Oct4-Sox2 complexes. Further, canonical Wnt signaling up-regulates the activity of the Pou5f1 distal enhancer via the Sox motif in mouse ESCs. When viewed in the context of published studies on Tcf3 and β-catenin mutants, our findings suggest that Tcf3 counters pluripotency by competition with Sox2 at these sites, and Tcf3 inhibition is blocked by β-catenin entry into this complex. Wnt pathway stimulation also triggers β-catenin association at regulatory elements with classic Lef/Tcf motifs associated with differentiation programs. The failure to activate these targets in the presence of a MEK/ERK inhibitor essential for mouse ESC culture suggests that MEK/ERK signaling and canonical Wnt signaling combine to mouse promote ESC differentiation. Triplicates of mouse embryonic stem cells cultured under the following conditions: 1) CHIR99021+PD0325901+LIF; 2) CHIR99021+PD0325901; 3) CHIR99021; 4) PD0325901; 5) DMSO

2013-03-01 | E-GEOD-43421 | biostudies-arrayexpress

Expression profiling of BRAFV600E melanoma cell lines upon RAF inhibition

Project description:Microarray expression analysis to identify global changes in transcription in response to RAF inhibition. Genes under RAF control were identified in a panel of BRAFV600E tumor cells, following the short-term inhibition of RAF using a pan-RAF kinase inhibitor, PLX4032 (Plexxikon). For comparison with changes in gene expression in response to MEK inhibition using PD0325901 (Pfizer), the following array data was referenced: (http://www.ncbi.nlm.nih.gov/geo/ (accession no. GSE10086)).

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