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

Oleksii S. Rukhlenko, Fahimeh Khorsand, Aleksandar Krstic, Jan Rozanc, Leonidas G. Alexopoulos, Nora Rauch, Keesha E. Erickson, William S. Hlavacek, Richard G Posner, Silvia Gómez-Coca, Edina Rosta, Cheree Fitzgibbon, David Matallanas, Jens Rauch, Walter Kolch, Boris N. Kholodenko

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
JournalCell Systems
DOIs
StateAccepted/In press - Jan 1 2018

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Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Histology
  • Cell Biology

Cite this

Rukhlenko, O. S., Khorsand, F., Krstic, A., Rozanc, J., Alexopoulos, L. G., Rauch, N., Erickson, K. E., Hlavacek, W. S., Posner, R. G., Gómez-Coca, S., Rosta, E., Fitzgibbon, C., Matallanas, D., Rauch, J., Kolch, W., & Kholodenko, B. N. (Accepted/In press). Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling. Cell Systems. https://doi.org/10.1016/j.cels.2018.06.002