MSK Team Finds a Way to Break Down Cancer’s Rogue DNA

A study from Memorial Sloan Kettering Cancer Center (MSK) has identified a structural weak point in extrachromosomal DNA, or ecDNA, a circular form of DNA found outside normal chromosomes in roughly 1 in 6 human cancers. ecDNA drives the amplification of cancer-causing genes and has been tied to faster tumor growth, treatment resistance, and worse survival outcomes, but how cancer cells manage to keep this unstable DNA intact had remained unclear. 

The lab of Agnel Sfeir, working with collaborators, has now mapped out a two-part protection system cancer cells rely on to prevent and repair breaks in ecDNA, while also showing that ecDNA carries a vulnerability that could potentially be targeted with existing drugs. The findings were published in Nature.

The team, co-led by David Billing and Monica Selvaraj traced ecDNA’s fragility to repetitive stretches of alternating T and A letters, known as TA repeats, which tend to fold into unusual, cross-shaped structures. These structures break easily, forcing the cancer cell to repair them quickly to keep the DNA intact.

“We were surprised to find that ecDNA has a built-in fragility,” Dr. Sfeir says. “The circular shape that allow genes to rapidly amplify and that give cancer cells a growth advantage are also inherently prone to breaking. That means cancer cells depend on repair to keep them intact, and that dependency is something we may be able to exploit.”

The researchers found that cancer cells lean on a repair protein called polymerase theta, or Polθ, to patch these breaks, while a second protein, FANCM, works upstream to keep the fragile structures from breaking in the first place. Together, FANCM smooths out the problem regions before damage occurs, and Polθ steps in to fix breaks once they do. When the team blocked Polθ with an experimental inhibitor, ecDNA grew unstable, accumulated damage, and was progressively lost across several cancer cell lines, including prostate, gastric, and colorectal cancers, while cells lacking ecDNA were largely unaffected. Sequencing data from human tumors showed the same TA repeat regions are common sites of DNA rearrangement across multiple cancer types, suggesting the vulnerability extends beyond the lab.

Because several Polθ inhibitors are already in clinical development, the findings point to a possible strategy for destabilizing ecDNA in hard-to-treat cancers, and pairing a Polθ inhibitor with FANCM depletion produced an even stronger effect, hinting at potential combination approaches. 

“This gives us a new way to think about targeting ecDNA,” says Dr. Sfeir. “There’s still much to learn, but we’re excited to see where the discovery of this vulnerability can take us.”