ArticleNature2016
Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling.
Article in Nature, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
59 citing papers in PubMed, 97 citations in OpenAlex.
- Modulating pseudokinase conformation from the ATP-binding site.Structure (London, England : 1993) · 2026Article
- Black Sheep: Pseudokinases Bucking the Trend to Reveal Non-Catalytic Kinase Functions.IUBMB life · 2026Review
- Allostery in Biomolecular Condensates.Journal of molecular biology · 2026Review
- Article
- Kinase suppressor of Ras 1 (KSR1) promotes liver carcinogenesis via activation of the RAS/RAF/MEK/ERK signaling pathway.JHEP reports : innovation in hepatology · 2025Article
- Targeting Kinase Suppressor of Ras 1 (KSR1) for Cancer Therapy.Pharmaceutics · 2025Review
- KSR2 Promotes Self-Renewal and Clonogenicity of Small Cell Lung Carcinoma.Molecular cancer research : MCR · 2025Article
- Fluorescence based live cell imaging identifies exon 14 skipped hepatocyte growth factor receptor (MET) degraders.RSC advances · 2025Article
- Recent Advances in Peptide Inhibitors Targeting Wild-Type Ras Protein Interactions in Cancer Therapy.International journal of molecular sciences · 2025Review
- Phenotypic profiling of small molecules using cell painting assay in HCT116 colorectal cancer cells.PloS one · 2025Article
- PPP3CB overexpression mediates EGFR TKI resistance in lung tumors via calcineurin/MEK/ERK signaling.Life science alliance · 2024Article
- Chemoproteomics Identifies State-Dependent and Proteoform-Selective Caspase-2 Inhibitors.Journal of the American Chemical Society · 2024Article
- Live-cell target engagement of allosteric MEKi on MEK-RAF/KSR-14-3-3 complexes.Nature chemical biology · 2024Article
- SOS1 and KSR1 modulate MEK inhibitor responsiveness to target resistant cell populations based on PI3K and KRAS mutation status.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Navigating the ERK1/2 MAPK Cascade.Biomolecules · 2023Review
- Does EGFR Signaling Mediate Orexin System Activity in Sleep Initiation?International journal of molecular sciences · 2023Review
- Activity-based protein profiling - finding general solutions to specific problems.Israel journal of chemistry · 2023Article
- Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species.Science advances · 2023Article
- Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance.Molecular systems biology · 2023Article
- Looking lively: emerging principles of pseudokinase signaling.Trends in biochemical sciences · 2022Review
Corrections and comments
- Commented on by
Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Deregulation of the Ras-mitogen activated protein kinase (MAPK) pathway is an early event in many different cancers and a key driver of resistance to targeted therapies. Sustained signalling through this pathway is caused most often by mutations in K-Ras, which biochemically favours the stabilization of active RAF signalling complexes. Kinase suppressor of Ras (KSR) is a MAPK scaffold that is subject to allosteric regulation through dimerization with RAF. Direct targeting of KSR could have important therapeutic implications for cancer; however, testing this hypothesis has been difficult owing to a lack of small-molecule antagonists of KSR function. Guided by KSR mutations that selectively suppress oncogenic, but not wild-type, Ras signalling, we developed a class of compounds that stabilize a previously unrecognized inactive state of KSR. These compounds, exemplified by APS-2-79, modulate KSR-dependent MAPK signalling by antagonizing RAF heterodimerization as well as the conformational changes required for phosphorylation and activation of KSR-bound MEK (mitogen-activated protein kinase kinase). Furthermore, APS-2-79 increased the potency of several MEK inhibitors specifically within Ras-mutant cell lines by antagonizing release of negative feedback signalling, demonstrating the potential of targeting KSR to improve the efficacy of current MAPK inhibitors. These results reveal conformational switching in KSR as a druggable regulator of oncogenic Ras, and further suggest co-targeting of enzymatic and scaffolding activities within Ras-MAPK signalling complexes as a therapeutic strategy for overcoming Ras-driven cancers.
Indexed as
Identifiers
What OpenQuestion holds
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.