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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.
Pubmed ID: 30007540 RIS Download
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This polyclonal targets IgG
View all literature mentionsThis polyclonal secondary targets IgG
View all literature mentionsThis monoclonal targets MAP Kinase, Activated (Diphosphorylated ERK-1&2)
View all literature mentionsThis polyclonal targets MAP Kinase (ERK-1 ERK-2) antibody produced in rabbit
View all literature mentionsCell line Mel JuSo is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line A-375 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line SK-MEL-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
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