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

Cell Systems
Oleksii S RukhlenkoBoris N Kholodenko

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.

Citations

Aug 3, 2019·Expert Opinion on Therapeutic Patents·Ruo-Jun ManHai-Liang Zhu
Oct 28, 2018·Essays in Biochemistry·Walter KolchColm J Ryan
Feb 28, 2020·Experimental and Therapeutic Medicine·Yan-Jun GuoLing-Ling Hu
Feb 13, 2020·International Journal of Molecular Sciences·Shannon LeeWalter Kolch
Apr 3, 2019·International Journal of Molecular Sciences·Paola SavoiaOttavio Cremona
Jun 1, 2019·NPJ Systems Biology and Applications·Daniel LillBoris N Kholodenko
Oct 16, 2018·Nucleic Acids Research·Rayees RahmanAvner Schlessinger
Feb 7, 2019·Scientific Reports·Afroza ShirinFrancesco Sorrentino
Apr 10, 2020·Oncogene·Tilman Brummer, Campbell McInnes
Jan 6, 2019·Biophysics Reviews·Ruth NussinovFeixiong Cheng
Jul 30, 2020·Scientific Reports·Beata HatTomasz Lipniacki
Oct 31, 2020·Current Opinion in Structural Biology·Oleksii RukhlenkoWalter Kolch
Feb 3, 2021·Mathematical Biosciences and Engineering : MBE·Kangbo Bao
Feb 18, 2020·Current Opinion in Structural Biology·Dénes BertaEdina Rosta
May 23, 2020·NPJ Systems Biology and Applications·Daniel LillBoris N Kholodenko
Mar 23, 2021·Journal of the American Chemical Society·Charles W MorganJason W Chin
May 27, 2021·Cell Reports·Boris N KholodenkoOleksii S Rukhlenko
Jul 1, 2021·PLoS Computational Biology·Cemal ErdemTimothy R Lezon
Oct 19, 2021·Molecular Systems Biology·Attila GaborJulio Saez-Rodriguez
Dec 29, 2021·PLoS Computational Biology·Robin SchmuckerTuomas Sandholm

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