Adaptive evolution of cancer-associated extrachromosomal DNA under therapeutic pressure: origin attribution, structural remodeling, mechanisms of acquired resistance, and therapeutic implications

Cancer-associated extrachromosomal DNA (ecDNA) increases intratumoral heterogeneity through non-Mendelian inheritance, high-copy-number oncogene amplification, and structural plasticity, thereby facilitating clonal selection under therapeutic pressure. Following chemotherapy or molecularly targeted therapy, ecDNA may undergo copy-number gain or loss, transient loss and re-emergence after treatment withdrawal, structural remodeling, and switching of amplification topology between extrachromosomal and intrachromosomal forms. These changes may reflect selection of pre-existing low-frequency ecDNA subclones, copy-number adjustment or structural remodeling of existing ecDNA, or treatment-associated de novo ecDNA formation. This review summarizes the roles of ecDNA in treatment adaptation and acquired resistance, with emphasis on origin attribution using longitudinal and multiregional sampling, breakpoint lineage tracing, single-cell tracking, and structure-specific functional validation. It also discusses potential vulnerabilities involving ecDNA biogenesis, replication stress, aberrant transcription, and ecDNA maintenance. Taken together, the evidence reviewed here is more consistent with treatment-mediated selection of pre-existing ecDNA subclones and copy-number adjustment or structural remodeling of existing ecDNA than with treatment-associated de novo ecDNA formation, for which direct in vivo evidence remains limited. Clinical translation will require standardized detection methods, reliable biomarkers for patient stratification, and clearly defined therapeutic windows.