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, posttranslational 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.
journal_name
Cell Systjournal_title
Cell systemsauthors
Rukhlenko OS,Khorsand F,Krstic A,Rozanc J,Alexopoulos LG,Rauch N,Erickson KE,Hlavacek WS,Posner RG,Gómez-Coca S,Rosta E,Fitzgibbon C,Matallanas D,Rauch J,Kolch W,Kholodenko BNdoi
10.1016/j.cels.2018.06.002subject
Has Abstractpub_date
2018-08-22 00:00:00pages
161-179.e14issue
2eissn
2405-4712issn
2405-4720pii
S2405-4712(18)30242-4journal_volume
7pub_type
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