Extrachromosomal DNA in Adaptive Tumour Evolution: Mechanisms Driving Plasticity, Drug Resistance and Precision Oncology

Abstract

Extrachromosomal DNA (ecDNA) has been identified as a critical component of tumour evolution, offering a dynamic genetic and regulatory landscape through which cancer cells can alter oncogene dosage, transcriptional states, and cellular phenotypes. Lacking centromeric and telomeric sequences, ecDNA is inherited in a non-Mendelian manner, resulting in substantial cell-to-cell variation in ecDNA copy number and composition. The aim of this review is to synthesize the biogenesis, molecular organization, and functional consequences of ecDNA, focusing on its role in tumour plasticity, adaptive evolution, therapeutic resistance and clinical translation. This narrative review synthesizes literature identified through structured searches of PubMed, Web of Science, Scopus, and Google Scholar covering publications from 2017 to August 2026, with emphasis on mechanistic and translational studies of cancer-associated ecDNA. Evidence indicates that ecDNA acts as a dynamic source of oncogenic amplification and cellular diversity, enabling rapid shifts in tumour states under selective pressure. These properties may help explain its association with disease progression and treatment failure, while emerging technologies are beginning to reveal opportunities for ecDNA-informed therapeutic intervention. Even with significant advances, one of the major problems is the ability to differentiate the biological effects specific to ecDNA from the effects that are due to high level amplification of oncogenes and genomic instability in general. An Integrative multi-dimensional approach will be crucial to uncover causal mechanisms and to advance the field of ecDNA-guided precision oncology.