Extrachromosomal DNA as a Driver of Therapeutic Escape in Cancer

Cancer remains a leading cause of death worldwide, and drug resistance is a major obstacle to durable treatment responses. Recent advances in cancer genomics have highlighted extrachromosomal DNA, large circular DNA molecules outside chromosomes. Once dismissed as a cytogenetic curiosity, extrachromosomal DNA (ecDNA) is now recognized as a potent and mechanistically distinct contributor to cancer progression and therapeutic escape. It is present in many cancers and is associated with poor outcomes, particularly in aggressive tumors. Non-Mendelian segregation, open chromatin architecture, transcriptional hub formation, and structural plasticity enable copy-number plasticity, intratumoral heterogeneity, and reversible transitions between drug-sensitive and drug-resistant states. These properties can promote resistance through increased expression or loss of drug-targeted oncogenes and amplification of alternative signaling components that bypass the inhibited pathways. Clinical studies indicate that therapeutic pressure shapes the ecDNA landscape and that ecDNA is associated with treatment failure and differential therapeutic responses. Here, we synthesize understanding of ecDNA biology and its role in drug resistance, review clinical evidence linking ecDNA to treatment failure, summarize emerging approaches for ecDNA detection, and discuss strategies targeting ecDNA-specific vulnerabilities and challenges in clinical translation. These insights position ecDNA as a dynamic contributor to adaptive resistance and a potential biomarker of vulnerability in precision oncology.