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Series GSE68230 Query DataSets for GSE68230
Status Public on Apr 24, 2015
Title Small molecule inhibition of ERK dimerization prevents tumorigenesis by Ras-ERK pathway oncogenes
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results.
 
Overall design A375p cells treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours. mRNA from A375p cells was extrated using RNeasy mini kit (Qiagen, Germany) according to the manufacturer's instructions. Cells were previously treated with10 μM of either DEL22379, SCH772984 or DMSO as a control for two hours.
 
Contributor(s) Crespo P
Citation(s) 26267534
Submission date Apr 24, 2015
Last update date May 15, 2019
Contact name Piero Crespo
E-mail(s) crespop@unican.es
Phone 942200959
Organization name IBBTEC
Street address c/Albert Einstein, 22
City SANTANDER
State/province Cantabria
ZIP/Postal code 39011
Country Spain
 
Platforms (1)
GPL18460 Illumina HiSeq 1500 (Homo sapiens)
Samples (10)
GSM1666042 PC01
GSM1666043 PC01b
GSM1666044 PC02
Relations
BioProject PRJNA282079
SRA SRP057629

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE68230_Control_DEL.csv.gz 364.9 Kb (ftp)(http) CSV
GSE68230_Control_SCH.csv.gz 365.9 Kb (ftp)(http) CSV
GSE68230_FPKM.txt.gz 1.1 Mb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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