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

Cell Syst. 2018 Aug 22;7(2):161-179.e14. doi: 10.1016/j.cels.2018.06.002. Epub 2018 Jul 11.


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.

Keywords: MAPK pathway; RAF dimerization; RAF inhibitors; conformational transitions of the DFG motif and αC helix; drug resistance; drug synergy; mathematical modeling; oncogenic RAS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Humans
  • MAP Kinase Signaling System / drug effects
  • Molecular Docking Simulation
  • Mutation / drug effects
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Multimerization / drug effects
  • Signal Transduction / drug effects*
  • Thermodynamics
  • raf Kinases / antagonists & inhibitors*
  • raf Kinases / chemistry
  • raf Kinases / metabolism
  • ras Proteins / genetics
  • ras Proteins / metabolism*


  • Protein Kinase Inhibitors
  • raf Kinases
  • ras Proteins