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Targeting extrachromosomal DNA in human cancers

Nature Reviews Drug Discovery (2026)Cite this article

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Abstract

Extrachromosomal DNAs (ecDNAs) are acentric circular DNA elements that frequently mediate oncogene amplification and genomic rearrangements in human cancers. Found across diverse adult and paediatric malignancies, ecDNA drives rapid tumour evolution, metabolic adaptation and treatment resistance. Its presence in precancerous lesions and association with poor outcome underscore the need for improved detection and therapeutic targeting. Recent advances have substantially expanded our understanding of ecDNA biology, revealing mechanisms underlying oncogene plasticity and treatment failure. This Review synthesizes key findings on ecDNA biology, the challenges faced by current therapeutic and detection approaches and the recent discoveries that point to emerging therapeutic vulnerabilities. We propose future directions to ecDNA-focused therapeutic development, including the utility of chemical proteomics approaches, and discuss efforts required to integrate ecDNA diagnostics into the clinic, presenting a roadmap from bench to bedside.

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Fig. 1: Oncogenic features of extrachromosomal DNAs and therapeutic vulnerabilities.
Fig. 2: Mechanisms of therapeutic resistance mediated by extrachromosomal DNA.
Fig. 3: Roadmap to extrachromosomal DNA drug discovery and clinical integration.

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Acknowledgements

This work was delivered as part of the eDyNAmiC team supported by the Cancer Grand Challenges partnership funded by Cancer Research UK CGCATF-2021/100012 (P.S.M. and H.Y.C.) and CGCATF-2021/100021 (B.F.C.) and the National Cancer Institute OT2CA278688 (P.S.M. and H.Y.C.), OT2CA278692 (B.F.C.) and R01 CA238249 (P.S.M. and B.F.C). H.Y. is a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation.

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Author notes

  1. Howard Y. Chang

    Present address: Amgen Research, South San Francisco, CA, USA

  2. These authors contributed equally: Ivy Tsz-Lo Wong, Hyerim Yi.

Authors and Affiliations

  1. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA

    Ivy Tsz-Lo Wong, Hyerim Yi & Paul S. Mischel

  2. Sarafan ChEM-H, Stanford University, Stanford, CA, USA

    Ivy Tsz-Lo Wong, Hyerim Yi & Paul S. Mischel

  3. Departments of Dermatology, Stanford University, Stanford, CA, USA

    Hyerim Yi & Howard Y. Chang

  4. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA

    Hyerim Yi & Howard Y. Chang

  5. Department of Genetics, Stanford University, Stanford, CA, USA

    Hyerim Yi & Howard Y. Chang

  6. Department of Chemistry, Scripps Research, La Jolla, CA, USA

    Bruno Melillo & Benjamin F. Cravatt

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Contributions

P.S.M., I.T.-L.W., H.Y., H.Y.C. and B.F.C. researched data for the article and contributed substantially to discussion of the content. All authors wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Benjamin F. Cravatt, Howard Y. Chang or Paul S. Mischel.

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Competing interests

P.S.M., H.Y.C. and B.F.C. are co-founders and advisers of Boundless Bio. P.S.M. is a co-founder of S1 Oncology. H.Y.C. is an employee and stockholder of Amgen as of 16 December 2024. H.Y.C. is a co-founder of Accent Therapeutics, Cartography Biosciences and Orbital Therapeutics and was an adviser of 10× Genomics, Arsenal Bio, Chroma Medicine, Exai Bio and Vida Ventures until 15 December 2024.

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Supplementary information

Glossary

Amplicon

A segment of DNA that is abnormally amplified at multiple high copies. Amplicon can locate either on a chromosome or extrachromosomally as ecDNA.

AmpliconArchitect

A computational tool to allow reconstruction of focally amplified regions using whole-genome sequencing data, with classification of amplicon structures to infer whether a focal amplification is of linear or circular nature.

Chromothripsis

A cellular process of randomly stitching shattered chromosomal pieces together to create new genetic rearrangement events.

Cytogenetics

The microscopic analysis of chromosomes for their number, structure and their influence on cellular behaviour, often in the context of genetic diseases and cancers.

Genomics England cohort

A large collection of whole-genome-sequenced tumours from patients with cancer across 13 UK National health Service Genomic Medicine Centers as part of the Genomics England (GEL) 100,000 Genomes Project (100kGP).

Isogenic cell line model

Isogenic cell lines are useful models to address whether a phenotype can be explained solely by the difference of where the amplicon is located (that is, extrachromosomal versus chromosomal). These are cell line pairs derived from the same tumour, hence sharing almost identical genetic background but with similar copy number and structure of the amplified locus encoded either on ecDNA (-EC/DM) or on chromosome (-HSR). Examples of isogenic cell line pairs are COLO320DM/HSR, GBM39EC/HSR, PC3DM/HSR and STA-NB-10/dmin/hsr.

Replication stress

A condition arising from disrupted DNA replication resulting in slow down or stalling of replication fork.

Tumour metaphases

A cytogenetic analysis method to allow spatial separation and visualization of individual chromosomes of a tumour cell. Mitotic arrest agent is treated to the sample to induce cell-cycle synchronization into metaphase, in which chromosomes are highly condensed for chromosome enumeration and structural evaluation.

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Wong, I.TL., Yi, H., Melillo, B. et al. Targeting extrachromosomal DNA in human cancers. Nat Rev Drug Discov (2026). https://doi.org/10.1038/s41573-025-01369-0

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