Researchers have uncovered new insights into “rogue DNA” that drives tumor growth, revealing a potential Achilles heel in the battle against cancer.
Some aggressive forms of cancer rely on rogue circles of DNA, which enable them to rapidly grow and resist treatment. Known as extrachromosomal DNA, or ecDNA, these unusual genetic fragments exist outside a cell’s normal chromosomes and occur in around one out of every six forms of human cancers.
These circles of DNA can also carry additional copies of certain genes linked to cancer, which offer tumors a significant advantage, while also contributing to treatment resistance and poorer patient outcomes.
Now, a recent study published in the journal Nature reveals that researchers at Memorial Sloan Kettering Cancer Center (MSK) and their collaborators have discovered a vulnerability linked to these “rogue” DNA structures, which could offer a previously unknown means of destabilizing ecDNA and treating some cancers.
An Achilles Heel in the Fight Against Cancer?
In their recent research, the team found that repetitive stretches of DNA known as TA repeats can fold into unusual cross-shaped structures, which also happen to produce fragile points where ecDNA is very prone to break.
“We were surprised to find that ecDNA has a built-in fragility,” said Agnel Sfeir, a researcher with MSK’s Sloan Kettering Institute. “The circular shape that allow genes to rapidly amplify and that give cancer cells a growth advantage are also inherently prone to breaking.”
Cancer cells, according to Sfeir and the team behind the new study, rely on two proteins to counteract this weakness. One is a human gene called Fanconi anemia, complementation group M, also known as FANCM, which helps prevent breaks by fixing DNA structures that exhibit problems. Another, known as polymerase theta, or Polθ, works to repair damage after breaks occur.
During studies, when researchers blocked Polθ with the help of an experimental inhibitor, damage was observed accumulating, and the ecDNA circles became very unstable. As the researchers monitored the resulting instability, they found that cancer cells were eventually unable to keep their hold and lost the ecDNA circles. By contrast, cells without ecDNA remained largely unaffected.
This effect, according to the research team, was observed across several varieties of cancers, including prostate, gastric, and colorectal cancer cell lines. Significantly, the researchers say that when Polθ was inhibited simultaneously as FANCM was depleted, the effect on cancer cells became even stronger.
The Path to Next-Gen Cancer Treatments
Right now, there are already several Polθ inhibitors that are under clinical development, which raises the possibility that researchers could eventually exploit this newly identified dependency to target cancers that thrive thanks to their reliance on ecDNA.
“This gives us a new way to think about targeting ecDNA,” Sfeir said. “There’s still much to learn, but we’re excited to see where the discovery of this vulnerability can take us.”
The team’s research was featured in a recent study, “MMEJ repair of breaks at TA repeats maintains ecDNA and cancer fitness,” published in the journal Nature on September 23, 2026.
Micah Hanks is the Editor-in-Chief and Co-Founder of The Debrief. A longtime reporter on science, defense, and technology with a focus on space and astronomy, he can be reached at micah@thedebrief.org. Follow him on X @MicahHanks, and at micahhanks.com.