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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:
 [1];  [1];  [1];  [2];  [3];  [1];  [4]; ORCiD logo [4];  [5];  [6];  [6];  [1];  [1];  [1];  [1];  [7]
  1. University College Dublin (Ireland)
  2. University of Luxembourg (Luxembourg); ProtATonce Ltd, Athens (Greece)
  3. ProtATonce Ltd, Athens (Greece); National Technical University of Athens (Greece)
  4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  5. Northern Arizona University, Flagstaff, AZ (United States)
  6. King's College London (United Kingdom)
  7. University College Dublin (Ireland); Yale University School of Medicine, New Haven, CT (United States)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC). Biological and Environmental Research (BER) (SC-23); USDOE
OSTI Identifier:
1564483
Alternate Identifier(s):
OSTI ID: 1467285
Report Number(s):
LA-UR-18-26812
Journal ID: ISSN 2405-4712
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Journal Article: Published Article
Journal Name:
Cell Systems
Additional Journal Information:
Journal Volume: 7; Journal Issue: 2; Journal ID: ISSN 2405-4712
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; Biological Science; RAF

Citation Formats

Rukhlenko, Oleksii S., Khorsand, Fahimeh, Krstic, Aleksander, Rozanc, Jan, Alexopoulos, Leonidas G., Rauch, Nora, Erickson, Keesha E., Hlavacek, William Scott, Posner, Richard G., Gomez-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. United States: N. p., 2018. Web. doi:10.1016/j.cels.2018.06.002.
Rukhlenko, Oleksii S., Khorsand, Fahimeh, Krstic, Aleksander, Rozanc, Jan, Alexopoulos, Leonidas G., Rauch, Nora, Erickson, Keesha E., Hlavacek, William Scott, Posner, Richard G., Gomez-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. United States. doi:10.1016/j.cels.2018.06.002.
Rukhlenko, Oleksii S., Khorsand, Fahimeh, Krstic, Aleksander, Rozanc, Jan, Alexopoulos, Leonidas G., Rauch, Nora, Erickson, Keesha E., Hlavacek, William Scott, Posner, Richard G., Gomez-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". United States. doi: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, Aleksander and Rozanc, Jan and Alexopoulos, Leonidas G. and Rauch, Nora and Erickson, Keesha E. and Hlavacek, William Scott and Posner, Richard G. and Gomez-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},
issn = {2405-4712},
number = 2,
volume = 7,
place = {United States},
year = {2018},
month = {7}
}

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

Citation Metrics:
Cited by: 7 works
Citation information provided by
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