Scientists have identified a potential new approach for treating aggressive cancers by targeting extrachromosomal DNA (ecDNA), rogue loops of genetic material that help tumors thrive and resist chemotherapy. A US-UK study, analyzing nearly 15,000 patients, revealed that many hard-to-treat cancers contain ecDNA, which is crucial for tumor survival and treatment resistance.
The research, which examined 39 different tumor types, found that 17.1% of cancers contained ecDNA. These loops of genetic code can make tumors harder to treat. The analysis shed light on how ecDNA drives cancer growth and resistance, leading researchers to identify a drug, already in early-stage clinical trials, with the potential to selectively destroy affected cells and prevent rapid resistance development.
The Role of ecDNA in Cancer Aggression
Normally, genes reside on 23 pairs of chromosomes within the cell nucleus. However, ecDNA fragments break off from chromosomes, forming circles that exist separately. These fragments carry cancer-driving genes and genes that suppress the immune system. The former promotes tumor growth, while the latter helps tumors evade the body’s natural defenses and resist immunotherapies.
The rapid and chaotic replication of ecDNA also fuels tumor growth. Unlike chromosomes, ecDNA can be passed on unevenly during cell division, increasing the tumor’s genetic diversity and resilience to anti-cancer drugs. According to Paul Mischel, a professor of pathology at Stanford University, this discovery is significant because it affects many people worldwide, particularly those with aggressive tumors that do not respond to current therapies.
Potential Therapeutic Strategies
The research indicates that CHK1 inhibitors may selectively destroy tumor cells containing ecDNA. In mouse experiments, a CHK1 inhibitor developed by Boundless Bio reduced tumors and prevented resistance when used with a traditional anti-cancer drug. "This is not just a discovery about what can make cancer so bad, it is actually pointing the way to a new set of therapies," Mischel stated. "There’s a path forward for developing new treatments because this type of DNA is different and it creates vulnerabilities that are different."
David Scott, the director of Cancer Grand Challenges at Cancer Research UK, emphasized that many aggressive cancers depend on ecDNA for survival and treatment resistance. Targeting ecDNA could potentially cut the lifeline of these tumors, transforming a poor prognosis into a treatable condition.
Charles Swanton, the deputy clinical director at the Francis Crick Institute in London, highlighted the importance of these circular DNA elements in cancer and their role in driving cancer cell fitness and immune evasion. He expressed hope that this work will pave the way for new approaches to limit their origins and impact, ultimately improving cancer drug sensitivity and patient outcomes.
