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

Journal Article · 01 August 2018 · Cell Systems

DOI: https://doi.org/10.1016/j.cels.2018.06.002 · OSTI ID:1564483

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

We report that 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. Finally, 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.

• Research Organization: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
• Sponsoring Organization: USDOE; USDOE Office of Science (SC). Biological and Environmental Research (BER) (SC-23)
• Grant/Contract Number: AC52-06NA25396
• OSTI ID: 1564483
• Alternate ID(s): OSTI ID: 1467285
• Report Number(s): LA-UR-18-26812; S2405471218302424; PII: S2405471218302424
• Journal Information: Cell Systems, Journal Name: Cell Systems Vol. 7 Journal Issue: 2; ISSN 2405-4712
• Publisher: ElsevierCopyright Statement
• Country of Publication: Niger
• Language: English