ArticleCell systems2018
Dissecting RAF Inhibitor Resistance by Structure-based Modeling Reveals Ways to Overcome Oncogenic RAS Signaling.
Article in Cell systems, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 73 citations in OpenAlex.
- A structure-based modeling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia.iScience · 2026Article
- A catalogue of missense and nonsense mutation abundances for the U.S. cancer patient population.medRxiv : the preprint server for health sciences · 2026Article
- Analysis of the Modulation of RAF Signaling by 14-3-3 Proteins.Bulletin of mathematical biology · 2026Article
- Dual RAF inhibition outperforms RAF-MEK combinations for suppressing ERK signaling in KRAS mutant cells.NPJ systems biology and applications · 2026Article
- Phase II Trial of Vemurafenib and Sorafenib Combination in AdvancedJournal of immunotherapy and precision oncology · 2026Article
- Artificial intelligence in mitotic checkpoint modeling: transforming our understanding of cellular division through machine learning and predictive biology.Briefings in bioinformatics · 2026Review
- Selective inhibition of BRAF and CRAF sensitizes NF1-deficient malignant peripheral nerve sheath tumors to MEK inhibitors.Molecular medicine (Cambridge, Mass.) · 2025Article
- Mathematical modeling suggests 14-3-3 proteins modulate RAF paradoxical activation.PLoS computational biology · 2025Article
- Systems Biology of the Cancer Cell.Annual review of biomedical engineering · 2025Review
- Cell-specific models reveal conformation-specific RAF inhibitor combinations that synergistically inhibit ERK signaling in pancreatic cancer cells.Cell reports · 2024Article
- Article
- Computational modeling of drug response identifies mutant-specific constraints for dosing panRAF and MEK inhibitors in melanoma.bioRxiv : the preprint server for biology · 2024Article
- Cancer research is not correlated with driver gene mutation burdens.Med (New York, N.Y.) · 2024Article
- Cell State Transition Models Stratify Breast Cancer Cell Phenotypes and Reveal New Therapeutic Targets.Cancers · 2024Article
- Signal execution modes emerge in biochemical reaction networks calibrated to experimental data.iScience · 2024Article
- Network-driven cancer cell avatars for combination discovery and biomarker identification for DNA damage response inhibitors.NPJ systems biology and applications · 2024Article
- Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node.Molecular oncology · 2024Review
- The Abundance of KRAS and RAS Gene Mutations in Cancer.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation.eLife · 2023Article
- BRAFScience advances · 2023Article
Corrections and comments
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Authors and funding
16 authors at 7 institutions in 5 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.