Findings published in Nature Communications by researchers at Penn State College of Medicine indicate that overexpression of the gene EXO1 can lead to DNA instability similar to that caused by BRCA mutations. This effect could potentially make certain tumors more susceptible to targeted chemotherapy treatments.

The gene EXO1 generates a protein that contributes to DNA repair processes. This gene is found to be overexpressed in 20% to 30% of breast and ovarian cancers, as well as in melanoma, testicular, cervical, and hepatobiliary cancers. Hepatobiliary cancers affect the liver, gall bladder, and bile duct. Cancer cells exhibiting high levels of EXO1 displayed behaviors consistent with cells possessing BRCA mutations, even when no BRCA mutation was present.

George-Lucian Moldovan, a professor of molecular and precision medicine, stated, "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." He added that drugs typically reserved for treating BRCA-mutant tumors, which have fewer side effects, might also be effective for EXO1 overexpressing tumors lacking BRCA mutations.

Researchers analyzed tumor data from The Cancer Genome Atlas, a National Cancer Institute cancer genomics program. They also conducted laboratory experiments using human cancer cells to investigate EXO1's role. During these experiments, researchers artificially increased EXO1 production in cancer cells to observe how excessive amounts of the protein impacted DNA. "Mechanistically, this overexpression does exactly what the loss of the BRCA pathway does in BRCA-mutant tumor cells," Moldovan said.

Excess EXO1 destabilizes newly formed DNA by expanding single-stranded DNA gaps and by degrading reversed replication forks. Alexandra Nusawardhana, the lead author of the study, said, "Regardless of which pathway, EXO1 overexpression leads to the generation and accumulation of toxic lesions in DNA, such as double strand breaks, which we ultimately think is what makes the tumor more sensitive to chemotherapy and increases cell death." The research also found that excessive EXO1 activity overwhelmed the protective mechanisms of BRCA genes even when those genes were functioning normally. EXO1 works in conjunction with the protein MRE11 to enlarge DNA gaps and create DNA breaks.

EXO1 overexpression is not an inherited trait. The researchers tested olaparib, a drug utilized against BRCA-mutant cancers, on tumors with elevated EXO1, finding that these tumors were sensitive to the treatment. Additionally, EXO1-overexpressing tumors responded to cisplatin, a chemotherapy drug. Moldovan said, "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." Claudia Nicolae, an assistant professor of molecular and precision medicine at Penn State College of Medicine, also contributed to the study, which received funding from the National Institutes of Health and Four Diamonds.