ArticleNature2014
Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma.
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 530 papers, 3 of them syntheses that pooled it.
What it found
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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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
530 citing papers in PubMed, 3 syntheses or guidelines pooled it, 899 citations in OpenAlex.
- Rebound regrowth phenomenon in patients with pediatric low-grade gliomas treated with MAPK inhibitors - a systematic review.Oncology reviews · 2026Pooled it
- The effects of dabrafenib and/or trametinib treatment in Braf V600-mutant glioma: a systematic review and meta-analysis.Neurosurgical review · 2024Pooled it
- The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis.Science advances · 2022Pooled 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 II Exploratory Study to Identify Biomarkers Predictive of Clinical Response to Regorafenib in Patients with Metastatic Colorectal Cancer Who Have Failed First-Line Therapy.International journal of molecular sciences · 2023Trial
- BAMM (BRAF Autophagy and MEK Inhibition in Melanoma): A Phase I/II Trial of Dabrafenib, Trametinib, and Hydroxychloroquine in Advanced BRAFV600-mutant Melanoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Trial
- Variant-Specific Landscape of Mutual Exclusivity Among BRAF, EGFR, and KRAS Oncogenes Reveals Overlap With Functionally Antagonistic Mutant Pairs.International journal of cancer · 2026Article
- PredictedInternational journal of molecular sciences · 2026Article
- MAPK Inhibitor-Tolerant Persister Cells in Melanoma: Mechanisms and Therapeutic Vulnerabilities.Cancer science · 2026Review
- SOX10-mediated regulation of the MiR-106a/363 cluster drives RAF inhibitor resistance in BRAF-mutant melanoma.Cellular and molecular life sciences : CMLS · 2026Article
- Acyclic Retinoid Attenuates STAT3 Signaling and Reduces In Vitro Growth of A375-Derived Dabrafenib Plus Trametinib-Resistant Melanoma Cells.International journal of molecular sciences · 2026Article
- A ZDHHC3-USP5-PTRF axis links palmitoylation to ferroptosis-associated phenotypes in melanoma.Cell death & disease · 2026Article
- Understanding and overcoming innate and acquired MAPK inhibition resistance in anaplastic thyroid cancer.Cell reports. Medicine · 2026Article
- Pre-existing cell states predict resistance to multiple treatments.Cell genomics · 2026Article
- ATR and PKMYT1 Inhibition Resensitizes a Subset of TNBC Patient-Derived Models to Carboplatin, Inducing Mitotic Catastrophe.Cancer research communications · 2026Article
- Article
- Sequential transcriptional waves and NF-κB-driven chromatin remodeling direct drug-induced dedifferentiation in cancer.Nature communications · 2026Article
- PHI-501, a dual inhibitor of RAF and DDR1/2, overcomes MAPK drug resistance in Melanoma.Cancer cell international · 2026Article
- Meta-analysis of the melanoma miRNome identifies consensus signatures of progression and prognosis regulating metabolic plasticity and stress resistance.bioRxiv : the preprint server for biology · 2026Article
- ERKed by too much signaling: from oncogenic driver to therapeutic vulnerability.Cellular and molecular life sciences : CMLS · 2026Review
470 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
25 authors at 4 institutions in 3 countries.
Funding
Abstract
Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably. In contrast, colon cancers that harbour the same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR). Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a chromatin-regulator-focused short hairpin RNA (shRNA) library, we find that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-β results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-β becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. We find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Our findings provide a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identify patients with EGFR-positive melanoma as a group that may benefit from re-treatment after a drug holiday.
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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.