期刊
CELL SYSTEMS
卷 7, 期 2, 页码 161-+出版社
CELL PRESS
DOI: 10.1016/j.cels.2018.06.002
关键词
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资金
- EU H2020 grant MSCA-IF-2016 SAMNets [750688]
- EU H2020 grant MSCA-IF-2016 SmartNanoTox [686098]
- EU H2020 grant MSCA-IF-2016 NanoCommons [731032]
- EU H2020 grant MSCA-IF-2016 Mel-Plex [642295]
- Science Foundation Ireland [14/IA/2395]
- NIH/NIGMS grant [R01GM111510]
- JDACS4C program of DOE
- NCI
- BBSRC [BB/N007700/1] Funding Source: UKRI
- EPSRC [EP/M022609/1, EP/L000253/1] Funding Source: UKRI
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, post-translational 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.
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