Extrachromosomal DNA, common in cancer, suggests a good drug target

Most of an animal cell’s DNA is stored in its nucleus, packaged into chromosomes that help maintain order. But cancer cells often carry another type of DNA: molecules separate from the rest of the genome that are highly expressed and anarchically copied and that often carry cancer-promoting sequences. Three papers in Nature from a Cancer Grand Challenges team explore this extrachromosomal DNA (ecDNA), reporting new insights into how it arises and is copied, and confers a new vulnerability.

In the first study, the researchers sequenced tumors from more than 14,000 people, and found that 17.1% contained ecDNA, with prevalence varying depending on a cancer’s tissue of origin. Advanced and metastatic tumors were more likely to contain ecDNA (DOI: 10.1038/s41586-024-08107-3).

In the second paper, the researchers explore how ecDNA is copied and inherited during cell replication. Surprisingly, ecDNAs with related functions can be inherited together, giving some cells a competitive edge (DOI: 10.1038/s41586-024-07861-8).

Finally, the researchers describe a way to exploit ecDNA’s high rate of replication and transcription: a conflict between DNA replication and RNA transcription (DOI: 10.1038/s41586-024-07802-5). When replication and transcription enzymes act at the same time, says senior author Howard Chang of Stanford University, “it’s like two trains running on the same track.” Cancer cells rely on the kinase CHK1 to manage stress from a high rate of collisions. The researchers observe that inhibition of CHK1 tends to harm cancer cells more than ordinary cells. A related start-up, Boundless Bio, is testing a CHK1 inhibitor in patients now.