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Effects of RAF inhibitors on PI3K/AKT signalling depend on mutational status of the RAS/RAF signalling axis

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Item Type:Article
Title:Effects of RAF inhibitors on PI3K/AKT signalling depend on mutational status of the RAS/RAF signalling axis
Creators Name:Fritsche-Guenther, R. and Witzel, F. and Kempa, S. and Brummer, T. and Sers, C. and Blüthgen, N.
Abstract:Targeted therapies within the RAS/RAF/MEK/ERK signalling axis become increasingly popular, yet cross-talk and feedbacks in the signalling network lead to unexpected effects. Here we look systematically into how inhibiting RAF and MEK with clinically relevant inhibitors result in changes in PI3K/AKT activation. We measure the signalling response using a bead-based ELISA, and use a panel of three cell lines, and isogenic cell lines that express mutant forms of the oncogenes KRAS and BRAF to interrogate the effects of the MEK and RAF inhibitors on signalling. We find that treatment with the RAF inhibitors have opposing effects on AKT phosphorylation depending on the mutational status of two important oncogenes, KRAS and BRAF. If these two genes are in wildtype configuration, RAF inhibitors reduce AKT phosphorylation. In contrast, if BRAF or KRAS are mutant, RAF inhibitors will leave AKT phosphorylation unaffected or lead to an increase of AKT phosphorylation. Down-regulation of phospho-AKT by RAF inhibitors also extends to downstream transcription factors, and correlates with apoptosis induction. Our results show that oncogenes rewire signalling such that targeted therapies can have opposing effects on parallel pathways, which depend on the mutational status of the cell.
Keywords:Sorafenib, Signal Transduction Networks, BRAF, KRAS, Colon Cancer
Source:Oncotarget
ISSN:1949-2553
Publisher:Impact Journals (U.S.A.)
Volume:7
Number:7
Page Range:7960-7969
Date:20 January 2016
Official Publication:https://doi.org/10.18632/oncotarget.6959
PubMed:View item in PubMed

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