Duke University School of Medicine researchers have discovered the keys to survival for a circular form of DNA that drives many aggressive cancers.
Found outside main chromosomes, ecDNA is known to lurk in the cancerous cells of one in three patients and is even more prevalent in deadly cancers like glioblastoma. Because ecDNA exists in many copies and has an open, loosely packed structure, it can help cancer cells quickly reproduce certain cancer-promoting genes.
By using large-scale genetic screens, conducting experiments in human cancer cell lines, and analyzing patient tumor tissue, scientists led by cancer biologist Zhao Zhang, PhD, discovered that two DNA-repair systems work together to create this dangerous form of DNA.
The work was pioneered by a former graduate student in Zhang’s lab, Oliver Chung, PhD, who collaborated with scientists in Duke’s Department of Pharmacology and Cancer Biology and Preston Robert Tisch Brain Tumor Center.
“Our work shows that the creation of ecDNA isn’t driven by a single DNA-repair pathway and points the way toward potential new treatments to slow cancer evolution and improve effectiveness of therapy,” said Zhang (known to many as ZZ), an associate professor of pharmacology and cancer biology.
The study, published March 11 in PNAS, points to new ideas for creating highly selective cancer treatments that can prevent treatment resistance. The researchers found that if either the BRCA1A protein complex or the LIG4 complex are disrupted, cancer cells can’t make the tumor-driving ecDNA.
Scientists have previously tried to develop drugs that block LIG4 to make cancer cells more sensitive to radiation. Those efforts didn’t succeed, but this study highlights the need to take a second look at LIG4 inhibitors, Zhang said.
While this work is still far away from clinical application, Zhang’s lab plans to develop new cancer therapies that target the LIG4 and BRCA1-A complexes and continue collaborations with Duke's brain tumor center.
Previously, the team had found that some components of both complexes aren’t required for normal cells to survive. So, the study suggests a way forward to create treatments that could target these proteins to fight cancer cells and prevent them from resisting treatment while minimizing side effects to normal cells.
Other Duke authors: Shun Yao, Ling Wang, Fu Yangk, Lauren Schier, Melissa Aldana, Christian Cerda-Smith, Haley M. Hutchinson, Kris C. Wood, Weijia Su, Mustafa Khasraw, and Lee Zou.
Funding: The Pew Biomedical Scholars Program, the Sontag Distinguished Scientist Award program, the National Institutes of Health, and the Cooperative Trials Group for Neuro-Oncology.