A DNA repair gene that goes into overdrive may inadvertently reveal how to treat some of the most aggressive cancers more effectively, according to new research from Penn State College of Medicine.
The discovery centers on EXO1, a gene normally tasked with maintaining and repairing DNA to prevent harmful mutations. But researchers found that when this protective gene is overactive, it causes the opposite problem: it damages DNA rather than protecting it, destabilizing the genome in ways that mimic hereditary cancer mutations.
The team discovered that EXO1 is overexpressed in 20 to 30 percent of breast and ovarian cancers, as well as melanoma, testicular, cervical and hepatobiliary cancers affecting the liver, gallbladder and bile duct. The work, published in Nature Communications, suggests this malfunction could become a powerful tool for matching patients to more targeted therapies.
"EXO1 overexpression leads to the generation and accumulation of toxic lesions in DNA, such as double strand breaks, which makes the tumor more sensitive to chemotherapy and increases cell death," explained Alexandra Nusawardhana, the lead author and recent doctorate recipient from Penn State College of Medicine.
How a Repair Tool Becomes a Weapon
Under normal conditions, EXO1 functions like molecular scissors, carefully trimming and repairing damaged DNA. But when present in excess, those scissors begin cutting DNA structures that should remain intact.
Laboratory experiments showed that excess EXO1 destabilizes newly formed DNA through two main pathways: expanding single-stranded DNA gaps and degrading reversed replication forks. Both processes erode genetic material and leave behind localized damage.
The critical finding is that tumors with abnormally high EXO1 levels behave much like cells carrying BRCA mutations, the well-known hereditary cancer risk genes. This similarity occurred even when no BRCA mutation was actually present, suggesting EXO1 overexpression can replicate dangerous DNA instability through a different biological route.
George-Lucian Moldovan, senior author and professor of molecular and precision medicine at Penn State, noted that EXO1 works alongside another protein called MRE11 to generate dangerous DNA breaks. "Mechanistically, this overexpression does exactly what the loss of the BRCA pathway does in BRCA-mutant tumor cells," he said.
The key distinction is that EXO1 overexpression is not inherited and does not appear to directly cause cancer on its own. Rather, it emerges as cancers develop, potentially representing an exploitable weakness.
Researchers analyzed tumor data from The Cancer Genome Atlas, a National Cancer Institute genomics program, and confirmed EXO1 elevation across multiple cancer types. Elevated EXO1 was especially associated with basal-like breast cancer, an aggressive subtype.
A Path to Precision Treatment
The therapeutic implications became clear when researchers tested olaparib, a drug commonly used against BRCA-mutant cancers that targets cellular DNA repair pathways. Tumors with elevated EXO1 were highly sensitive to the treatment, responding similarly to BRCA-mutant cancers.
EXO1-overexpressing tumors also responded to cisplatin, a widely used chemotherapy drug, raising the possibility that lower doses might achieve comparable tumor shrinkage with reduced side effects.
"EXO1 doesn't predict cancer risk, but it could potentially serve as a biomarker to help predict which patients are more likely to respond to certain chemotherapy treatments, leading to more personalized therapies," Moldovan said. "The same drugs that are reserved for treating BRCA-mutant tumors and that have fewer side effects could potentially be used to treat EXO1 overexpressing tumors, which don't have BRCA mutations."
Because EXO1 overexpression appears in a wider range of tumors than BRCA mutations alone, it could become a more broadly applicable biomarker for treatment decisions across multiple cancer types. This aligns with a growing shift in oncology toward tumor profiling rather than tissue-based classifications.
"We shouldn't treat cancers based on what tissue they come from but based on the landscape of the genetic mutations present in the tumors," Moldovan said. "That would result in high efficiency treatment. That's the future of cancer treatment."
The research team plans to continue studying EXO1 with the goal of launching clinical trials in patients whose tumors overexpress the gene. Claudia Nicolae, assistant professor of molecular and precision medicine at Penn State College of Medicine, also contributed to the study.
Author Jessica Williams: "If EXO1 proves to be a reliable treatment predictor, it could open precision therapy options for patients who wouldn't qualify for current BRCA-targeted drugs, potentially expanding the reach of some of medicine's most effective cancer treatments."
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