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

Abstract

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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; USDOE Office of Science (SC). Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1564483
Alternate Identifier(s):
OSTI ID: 1467285
Report Number(s):
LA-UR-18-26812
Journal ID: ISSN 2405-4712; S2405471218302424; PII: S2405471218302424
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Published Article
Journal Name:
Cell Systems
Additional Journal Information:
Journal Name: Cell Systems Journal Volume: 7 Journal Issue: 2; Journal ID: ISSN 2405-4712
Publisher:
Elsevier
Country of Publication:
Niger
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science; RAF

Citation Formats

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, and Kholodenko, Boris N. Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling. Niger: N. p., 2018. Web. doi:10.1016/j.cels.2018.06.002.
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. Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling. Niger. doi:https://doi.org/10.1016/j.cels.2018.06.002
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, and Kholodenko, Boris N. Wed . "Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling". Niger. doi:https://doi.org/10.1016/j.cels.2018.06.002.
@article{osti_1564483,
title = {Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling},
author = {Rukhlenko, Oleksii S. and Khorsand, Fahimeh and Krstic, Aleksandar and Rozanc, Jan and Alexopoulos, Leonidas G. and Rauch, Nora and Erickson, Keesha E. and Hlavacek, William S. and Posner, Richard G. and Gómez-Coca, Silvia and Rosta, Edina and Fitzgibbon, Cheree and Matallanas, David and Rauch, Jens and Kolch, Walter and Kholodenko, Boris N.},
abstractNote = {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.},
doi = {10.1016/j.cels.2018.06.002},
journal = {Cell Systems},
number = 2,
volume = 7,
place = {Niger},
year = {2018},
month = {8}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: https://doi.org/10.1016/j.cels.2018.06.002

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Cited by: 7 works
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