New research published in Nature demonstrates how extrachromosomal DNA (ecDNA) drives tumor evolution by promoting oncogene expression and creating novel regulatory circuits. The studies, part of the Cancer Grand Challenges' Team eDyNAmiC project, reveal potential therapeutic vulnerabilities in ecDNA-containing cancers.
The Role of ecDNA in Cancer Progression
ecDNA's acentric structure leads to intratumoral genetic heterogeneity, elevated copy number, and rapid tumor evolution. These circular molecules can cluster in the nucleus, generating new enhancer-promoter interactions and evolving gene regulatory relationships. Analysis of 14,778 patients with 39 tumor types from the 100,000 Genomes Project showed that 17.1% of tumor samples contained ecDNA, which was associated with poor survival even after adjusting for underlying genome instability.
Co-Segregation and Cooperation of ecDNAs
Single-cell sequencing, imaging, and evolutionary modeling across multiple cancer types revealed that ecDNA species co-occur in cancer cells and co-segregate during mitosis. This coordinated inheritance stabilizes oncogene cooperation and novel gene regulatory circuits, leading to the co-amplification of multiple oncogenes and the diversification of cancer genomes. The research highlights a "jackpot effect" where heterogeneous ecDNAs cooperate to enhance cancer's adaptability.
Targeting ecDNA: A Novel Therapeutic Approach
Further research indicates that ecDNA provides a transcriptional advantage, driving tumor evolution through massive oncogene expression and rapid genome adaptation. This process leads to transcription-replication conflicts, causing DNA breaks. Cancer cells depend on CHK1, an S-phase checkpoint kinase activator, to mitigate these effects. The study demonstrated that BBI-2779, a CHK1 inhibitor, preferentially destroys tumor cells containing ecDNA and induces significant tumor regression in mice with gastric cancer.
