Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling
|Title:||Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling||Authors:||Rukhlenko, Oleksii S.; Khorsand, Fahimeh; Krstic, Aleksandar; Rauch, Nora; Fitzgibbon, Cheree; Matallanas, David; Rauch, Jens; Kolch, Walter; Kholodenko, 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 inhibitors; Drug resistance; Mathematical modeling; MAPK pathway; Oncogenic RAS; Drug synergy; RAF dimerization; Conformational 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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