Memorial Sloan Kettering (opens in new tab) Cancer Center researchers reported Wednesday that extrachromosomal DNA (ecDNA)—circular DNA outside chromosomes found in roughly one in six human cancers—relies on a two-part protection system that can be disrupted in the lab, according to an MSK news release summarizing a Nature (opens in new tab) paper published Sept. 23.
ecDNA amplifies cancer-driving genes and is linked to faster growth, therapy resistance, and poorer survival. The lab of Agnel Sfeir, with co-first authors David Billing and Monica Selvaraj, found fragile TA-repeat stretches that form unusual DNA structures. Protein FANCM helps prevent breaks there; polymerase theta (Polθ) repairs breaks that still occur via microhomology-mediated end joining.
When the team blocked Polθ with an experimental inhibitor (RP-2119 from Repare Therapeutics), ecDNA accumulated damage and was progressively lost from cancer cells, while cells without ecDNA were largely unaffected, MSK said. Effects appeared across prostate, gastric, and colorectal cancer cell lines. Combining Polθ blockade with FANCM depletion strengthened the effect in the reported experiments.
Tumor sequencing datasets showed rearrangements clustering at the same TA-repeat regions, the release said. Several Polθ inhibitors are already in clinical development, but The Event Log treats patient benefit as unproven until trial results are published. Disclosures note Sfeir’s past ties to Repare and co-authors who are former Repare employees.