Extrachromosomal DNA–Driven Oncogene Dosage Heterogeneity Promotes Rapid Adaptation to Therapy in MYCN -Amplified Cancers

ecDNA-driven tumor genome evolution provides a major challenge to curative cancer therapies. We demonstrate that ecDNA copy-number dynamics drives treatment resistance by promoting oncogene dosage-dependent phenotypic heterogeneity in MYCN-amplified cancers. Exploiting phenotype-specific vulnerabilities of ecDNA cells, therefore, presents a powerful strategy to overcome treatment resistance. See related commentary by Korsah, p. 1979.