{"entity":{"id":"idea-ecdna-targeting","kind":"idea","name":"Attack extrachromosomal DNA, the engine of oncogene amplification","aka":[],"tldr":"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).","asOf":"2026-09-08","links":[{"label":"Turner et al., Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity (Nature 2017)","url":"https://doi.org/10.1038/nature21356"}],"tags":["mechanism","open-question"],"related":[],"cancers":["glioblastoma","sarcoma","gastric"],"sections":[],"technologies":["wes-wgs","liquid-biopsy"],"targets":["egfr","cdk4-6"],"drugs":[],"companies":[],"institutions":["stanford","cruk"],"pathways":["chromosomal-instability","replication-stress","clonal-evolution"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-turner-nature","paper-egfr-gastric-eur-j-cancer-2001","paper-egfr-glioblastoma-mol-oncol-2018","paper-egfr-glioblastoma-sci-signal-2009"],"journals":[],"dependsOn":[],"notes":[],"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.","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"},"route":"/ideas/idea-ecdna-targeting/","neighbours":{"cancer":[{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"},{"id":"sarcoma","kind":"cancer","name":"Sarcomas (soft tissue, bone, GIST)","route":"/cancers/sarcoma/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"cdk4-6","kind":"target","name":"CDK4/6","route":"/targets/cdk4-6/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"}],"institution":[{"id":"cruk","kind":"institution","name":"Cancer Research UK","route":"/institutions/cruk/"},{"id":"stanford","kind":"institution","name":"Stanford Health Care / Stanford Cancer Institute","route":"/institutions/stanford/"}],"pathway":[{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"id":"replication-stress","kind":"pathway","name":"DNA replication stress","route":"/pathways/replication-stress/"}],"paper":[{"id":"paper-egfr-gastric-eur-j-cancer-2001","kind":"paper","name":"EGFR and cancer prognosis","route":"/key-papers/paper-egfr-gastric-eur-j-cancer-2001/"},{"id":"paper-egfr-glioblastoma-mol-oncol-2018","kind":"paper","name":"Emerging functions of the EGFR in cancer","route":"/key-papers/paper-egfr-glioblastoma-mol-oncol-2018/"},{"id":"paper-turner-nature","kind":"paper","name":"Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity","route":"/key-papers/paper-turner-nature/"},{"id":"paper-egfr-glioblastoma-sci-signal-2009","kind":"paper","name":"Oncogenic EGFR signaling networks in glioma","route":"/key-papers/paper-egfr-glioblastoma-sci-signal-2009/"}]}}