ArticleScience advances2019
BRAF inhibitors promote intermediate BRAF(V600E) conformations and binary interactions with activated RAS.
Article in Science advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
27 citing papers in PubMed, 46 citations in OpenAlex.
- DUSP1 is a key driver of disease persistence and potential therapeutic target in hairy cell leukemia.Blood advances · 2026Article
- Targeted design, synthesis, molecular dynamics, ADME and in -vitro anticancer assessment of oxo-tetrahydro-pyrimidin-benzenesulfonamide hybrids as potential BRAFScientific reports · 2025Article
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- Oncogenic non-V600 mutations evade the regulatory machinery of RAF including the Cdc37/Hsp90 chaperone and the 14-3-3 scaffold.Theranostics · 2025Article
- Article
- Identification of an H-Ras nanocluster disrupting peptide.Communications biology · 2024Article
- Article
- Novel RAF-directed approaches to overcome current clinical limits and block the RAS/RAF node.Molecular oncology · 2024Review
- A comprehensive study of SARS-CoV-2 main protease (MbioRxiv : the preprint server for biology · 2023Article
- BRAFScience advances · 2023Article
- Disruptor: Computational identification of oncogenic mutants disrupting protein-protein and protein-DNA interactions.Communications biology · 2023Article
- Analysis of RAS and drug induced homo- and heterodimerization of RAF and KSR1 proteins in living cells using split Nanoluc luciferase.Cell communication and signaling : CCS · 2023Article
- Tracking and blocking interdependencies of cellular BRAF-MEK oncokinase activities.PNAS nexus · 2023Article
- Investigating the conformational landscape of AlphaFold2-predicted protein kinase structures.Bioinformatics advances · 2023Article
- Kinase perturbations redirect mitochondrial function in cancer.Bioenergetics communications · 2022Article
- Resistor: An algorithm for predicting resistance mutations via Pareto optimization over multistate protein design and mutational signatures.Cell systems · 2022Article
- Physiological Cell Culture Media Tune Mitochondrial Bioenergetics and Drug Sensitivity in Cancer Cell Models.Cancers · 2022Article
- Article
- Classical RAS proteins are not essential for paradoxical ERK activation induced by RAF inhibitors.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif.Science signaling · 2021Article
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
Abstract
Oncogenic BRAF mutations initiate tumor formation by unleashing the autoinhibited kinase conformation and promoting RAS-decoupled proliferative RAF-MEK-ERK signaling. We have engineered luciferase-based biosensors to systematically track full-length BRAF conformations and interactions affected by tumorigenic kinase mutations and GTP loading of RAS. Binding of structurally diverse αC-helix-OUT BRAF inhibitors (BRAFi) showed differences in specificity and efficacy by shifting patient mutation-containing BRAF reporters from the definitive opened to more closed conformations. Unexpectedly, BRAFi engagement with the catalytic pocket of V600E-mutated BRAF stabilized an intermediate and inactive kinase conformation that enhanced binary RAS:RAF interactions, also independently of RAF dimerization in melanoma cells. We present evidence that the interference with RAS interactions and nanoclustering antagonizes the sequential formation of drug-induced RAS:RAF tetramers. This suggests a previously unappreciated allosteric effect of anticancer drug-driven intramolecular communication between the kinase and RAS-binding domains of mutated BRAF, which may further promote paradoxical kinase activation and drug resistance mechanisms.
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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.