ecDNA Inheritance Supports Tumor Heterogeneity and Evolution

Extrachromosomal DNA (ecDNA) oncogene amplification is common in human cancers and is associated with poor outcome, aggressive tumor growth, and drug resistance. It has been postulated that some of the paradoxical features involved in tumor clonal evolution can be explained by ecDNA amplification, as ecDNA can be unequally segregated during cell division due to their lack of centromeres. However, the impact of nonchromosomal oncogene inheritance on intratumoral genetic heterogeneity is not yet fully understood. To address this, Lange, Rose, Chen, and colleagues used integrated computer simulations, mathematical modeling, and CRISPR-based ecDNA tagging along with live-cell imaging to show that the inheritance of ecDNA is random and leads to extensive ecDNA copy-number heterogeneity. Direct comparison of extrachromosomal and chromosomal dynamics in the same cell population after drug treatment indicated a dose-dependent rise in dihydrofolate reductase (DHFR) ecDNA copy number in response to methotrexate treatment (targets DHFR), suggesting a robust selective advantage for cells with specific ecDNA copy-number gain. Moreover, evaluation of ecDNA and its ability to affect tumor stress adaptation revealed that reduction of glucose from the culture medium of glioblastoma (GBM) cells that were heavily dependent on glycolysis did not affect GBM cells with high ecDNA copies of the EGFRvIII gain-of-function mutation, while cells without this high ecDNA copy number were sensitive to glucose withdrawal and had reduced cell growth. Additionally, these same GBM cells with high EGFRvIII ecDNA copy number were also resistant to erlotinib treatment. These results were similarly extended to vincristine treatment of cell lines with MYCN amplification as well as CDK4/6 inhibitor treatment of cell lines with high CDK4 copy number. In summary, this study shows that ecDNA shapes tumor cell evolution and adaptation as well as supports ecDNA oncogene amplification as an underlying mechanism behind poor clinical activity of targeted therapies. Together, these results suggest that treatment of high-ecDNA cancers may require targeting this unique adaptability moving forward.

Lange JT, Rose JC, Chen CY, Pichugin Y, Xie L, Tang J, et al. The evolutionary dynamics of extrachromosomal DNA in human cancers. Nat Genet 2022;54:1527–33.

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