Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling

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Title: Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling
Authors: Rukhlenko, Oleksii S.Khorsand, FahimehKrstic, AleksandarRauch, NoraFitzgibbon, ChereeMatallanas, DavidRauch, JensKolch, WalterKholodenko, Boris N.et al.
Permanent link: http://hdl.handle.net/10197/10852
Date: 22-Aug-2018
Online since: 2019-07-08T08:47:13Z
Abstract: Clinically used RAF inhibitors are ineffective in RAS-mutant tumors because they enhance homo- and heterodimerization of RAF kinases, leading to paradoxical activation of ERK signaling. Overcoming enhanced RAF dimerization and the resulting resistance is a challenge for drug design. Combining multiple inhibitors could be more effective, but it is unclear how the best combinations can be chosen. We built a next-generation mechanistic dynamic model to analyze combinations of structurally different RAF inhibitors, which can efficiently suppress MEK/ERK signaling. This rule-based model of the RAS/ERK pathway integrates thermodynamics and kinetics of drug-protein interactions, structural elements, post-translational modifications and cell mutational status as model rules to predict RAF inhibitor combinations for inhibiting ERK activity in oncogenic RAS and/or BRAFV600E backgrounds. Predicted synergistic inhibition of ERK signaling was corroborated by experiments in mutant NRAS, HRAS and BRAFV600E cells, and inhibition of oncogenic RAS signaling was associated with reduced cell proliferation and colony formation.
Funding Details: European Commission Horizon 2020
Science Foundation Ireland
Type of material: Journal Article
Publisher: Elsevier BV
Journal: Cell Systems
Volume: 7
Issue: 2
Start page: 161
End page: 179.e14
Copyright (published version): 2018 Elsevier
Keywords: RAF inhibitorsDrug resistanceMathematical modelingMAPK pathwayOncogenic RASDrug synergyRAF dimerizationConformational transitions of the DFG motif and αC helix
DOI: 10.1016/j.cels.2018.06.002
Language: en
Status of Item: Peer reviewed
Appears in Collections:Medicine Research Collection

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