# Attack extrachromosomal DNA, the engine of oncogene amplification

Source: https://onco.cc/ideas/idea-ecdna-targeting/  
OnCo record `idea-ecdna-targeting` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Aggressive glioblastomas, sarcomas and gastric cancers keep amplified cancer genes such as EGFR, MYC, MDM2 and CDK4 on free-floating DNA circles (ecDNA) whose copy number rises and falls quickly, letting the tumour dial resistance up and down. Cells carrying ecDNA depend on CHK1, giving a first drug target.

## Summary

ecDNA carries EGFR, MYC, MDM2, and CDK4 amplicons in glioblastoma, sarcoma, and gastric cancer, associates with shorter survival, and enables rapid drug resistance by copy-number fluctuation. The eDyNAmiC Cancer Grand Challenge team reported CHK1 dependence and transcription-replication conflicts in ecDNA+ cells (2024).

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Tags: mechanism; open-question
- Hypothesis: ecDNA-positive tumours are selectively sensitive to CHK1 inhibition combined with the amplified-oncogene inhibitor, and ecDNA status detectable by WGS or cfDNA identifies responders.
- Rationale: Preclinical CHK1 sensitivity, an ecDNA detection assay (AmpliconArchitect) applicable to routine WGS, and the failure of oncogene inhibitors alone in ecDNA-driven tumours.
- Proposed test: Phase 1/2 of a CHK1 inhibitor plus targeted agent in ecDNA-positive EGFR-amplified glioblastoma and MDM2/CDK4-amplified sarcoma, with ecDNA burden in cfDNA as a pharmacodynamic marker.
- Maturity: preclinical-evidence

## Sources

- Turner et al., Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity (Nature 2017): https://doi.org/10.1038/nature21356

## Connected records

- cancers: [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [Glioma & glioblastoma](https://onco.cc/cancers/glioblastoma/), [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/)
- technologies: [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [CDK4/6](https://onco.cc/targets/cdk4-6/), [EGFR](https://onco.cc/targets/egfr/)
- institutions: [Cancer Research UK](https://onco.cc/institutions/cruk/), [Stanford Health Care / Stanford Cancer Institute](https://onco.cc/institutions/stanford/)
- pathways: [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/), [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [DNA replication stress](https://onco.cc/pathways/replication-stress/)
- key papers: [EGFR and cancer prognosis](https://onco.cc/key-papers/paper-egfr-gastric-eur-j-cancer-2001/), [Emerging functions of the EGFR in cancer](https://onco.cc/key-papers/paper-egfr-glioblastoma-mol-oncol-2018/), [Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity](https://onco.cc/key-papers/paper-turner-nature/), [Oncogenic EGFR signaling networks in glioma](https://onco.cc/key-papers/paper-egfr-glioblastoma-sci-signal-2009/)

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