ArticleCancer discovery2022
Plasticity of Extrachromosomal and Intrachromosomal BRAF Amplifications in Overcoming Targeted Therapy Dosage Challenges.
Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 76 citations in OpenAlex.
- Unraveling the lexicon of complex mutational phenomena in human cancers.Nature cancer · 2026Review
- Extrachromosomal DNA as a platform for epigenetic reprogramming in cancer.Molecular cancer · 2026Review
- Extrachromosomal DNA in urothelial carcinoma: mechanisms and clinical applications.Nature reviews. Urology · 2026Review
- Plasticity of extrachromosomal DNA segregation during drug adaptation.Nature communications · 2026Article
- scAmp enables focal gene amplification analysis from single-cell data.Nature communications · 2026Article
- Detecting and reconstructing breakage-fusion-bridge cycles from long-read sequencing using BFBArchitect.Bioinformatics (Oxford, England) · 2026Article
- Translating ferroptosis into oncology: challenges, opportunities and future directions.Nature reviews. Clinical oncology · 2026Review
- Targeting extrachromosomal DNA in human cancers.Nature reviews. Drug discovery · 2026Review
- The potential clinical implications of extrachromosomal circular DNA as a biomarker.Genes & diseases · 2026Review
- Extrachromosomal DNA Gives Cancer a New Evolutionary Pathway.Research square · 2026Article
- Review
- scAmp analyzes focal gene amplifications at single-cell resolution.bioRxiv : the preprint server for biology · 2026Article
- Extrachromosomal DNA and cancer: function, formation, and clinical implications.Journal of experimental & clinical cancer research : CR · 2026Review
- Innate immune sensing via the cGAS-STING pathway restricts extrachromosomal DNA-driven tumorigenesis.bioRxiv : the preprint server for biology · 2026Article
- Epigenetic priming promotes tyrosine kinase inhibitor resistance and oncogene amplification.Nature structural & molecular biology · 2026Article
- Drug-tolerant persister cells in cancer: bridging the gaps between bench and bedside.Nature communications · 2025Review
- ecDNA-driven oncogene super-expressors shape immunoevasive tumor microenvironment.bioRxiv : the preprint server for biology · 2025Article
- DNA damage response pathway is a promising therapeutic target for extrachromosomal DNA-positive tumours.Clinical and translational medicine · 2025Article
- A Guide to Extrachromosomal DNA: Cancer's Dynamic Circular Genome.Cancer discovery · 2025Review
- EGFR influences the resistance to targeted therapy in BRAFArchives of dermatological research · 2025Article
Corrections and comments
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Authors and funding
31 authors at 6 institutions in 2 countries.
Funding
Abstract
Focal amplifications (FA) can mediate targeted therapy resistance in cancer. Understanding the structure and dynamics of FAs is critical for designing treatments that overcome plasticity-mediated resistance. We developed a melanoma model of dual MAPK inhibitor (MAPKi) resistance that bears BRAFV600 amplifications through either extrachromosomal DNA (ecDNA)/double minutes (DM) or intrachromosomal homogenously staining regions (HSR). Cells harboring BRAFV600E FAs displayed mode switching between DMs and HSRs, from both de novo genetic changes and selection of preexisting subpopulations. Plasticity is not exclusive to ecDNAs, as cells harboring HSRs exhibit drug addiction-driven structural loss of BRAF amplicons upon dose reduction. FA mechanisms can couple with kinase domain duplications and alternative splicing to enhance resistance. Drug-responsive amplicon plasticity is observed in the clinic and can involve other MAPK pathway genes, such as RAF1 and NRAS. BRAF FA-mediated dual MAPKi-resistant cells are more sensitive to proferroptotic drugs, extending the spectrum of ferroptosis sensitivity in MAPKi resistance beyond cases of dedifferentiation. SIGNIFICANCE: Understanding the structure and dynamics of oncogene amplifications is critical for overcoming tumor relapse. BRAF amplifications are highly plastic under MAPKi dosage challenges in melanoma, through involvement of de novo genomic alterations, even in the HSR mode. Moreover, BRAF FA-driven, dual MAPKi-resistant cells extend the spectrum of resistance-linked ferroptosis sensitivity. This article is highlighted in the In This Issue feature, p. 873.
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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.