ArticleNature2010
COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.
Article in Nature, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02583516 (A Randomized Phase II Study of Vemurafenib Plus Cobimetinib Continuous Versus Intermittent, in Previously Untreated BRAFV600- Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma), which is not on this map. Cited by 791 papers, 1 of them a synthesis that pooled it.
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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.
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.
A Randomized Phase II Study of Vemurafenib Plus Cobimetinib Continuous Versus Intermittent, in Previously Untreated BRAFV600- Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma
Who cites it
791 citing papers in PubMed, 1 synthesis or guideline pooled it, 1,444 citations in OpenAlex.
- Causal effects of blood cells on breast cancer: Evidence from bidirectional Mendelian randomization combined with meta-analysis.Medicine · 2025Pooled it
- Longitudinal Genomic Analysis to Fine-tune Targeted Therapy: Results of the Phase II LOGIC 2 Trial in Patients with BRAFV600-Mutant Metastatic Melanoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- A phase I/II study of bevacizumab, irinotecan and erlotinib in children with progressive diffuse intrinsic pontine glioma.Journal of neuro-oncology · 2021Trial
- From MAPK Reactivation to Response: Clinical Approaches Targeting BRAF/MEK Resistance in Melanoma.American journal of clinical dermatology · 2026Review
- New and emerging strategies for targeting cancers: Challenges and opportunities (Review).Oncology letters · 2026Review
- Free energy perturbation and machine learning-assisted identification of potential MAP3K8 hit molecules: a comprehensive structure- and ligand-based studies.Molecular diversity · 2026Article
- Gene fusions in melanocytic lesions: an updated comprehensive review.Journal of pathology and translational medicine · 2026Article
- Integrative multi-omics defines melanoma drug response networks and ARID1A-dependent resistance mechanisms.Molecular systems biology · 2026Article
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- Activating protein kinases to treat diseases: Current understanding and future challenges.Acta pharmaceutica Sinica. B · 2026Review
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- Drug screening in 3D microtumors reveals DDR1/2-MAPK12-GLI1 as a vulnerability in cancer-associated fibroblasts.Cell reports. Medicine · 2025Article
- The role of SPRED1 mutation in melanoma.European journal of medical research · 2025Review
- Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells.Nature communications · 2025Article
- Transcriptome-wide decoding the roles of aberrant splicing in melanoma MAPK-targeted resistance evolution.EMBO reports · 2025Article
- Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer.British journal of cancer · 2025Article
- Morphological map of under- and overexpression of genes in human cells.Nature methods · 2025Article
- MEK Inhibition in Glioblastoma: Current Perspectives and Future Directions.International journal of molecular sciences · 2025Review
- Nitroglycerin-responsive gene switch for the on-demand production of therapeutic proteins.Nature biomedical engineering · 2025Article
- CD28 is superior to 4-1BB costimulation in generating CAR-NK cells for tumor immunotherapy.Experimental hematology & oncology · 2025Article
731 more citing papers are in PubMed but not listed here.
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Authors and funding
35 authors at 7 institutions in 2 countries.
Funding
Abstract
Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ∼600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
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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.