Scientists have discovered that a powerful cancer-associated protein does more than just promote tumor growth. It also helps cancer cells survive by repairing damaged DNA, a discovery that could ultimately improve treatments for the most deadly cancers.
This study genes and developmentfocused on MYC, a protein that is abnormally active in most human cancers. Researchers at Oregon Health and Science University (OHSU) have discovered that MYC directly helps repair dangerous breaks in DNA, allowing tumor cells to recover from chemotherapy and other treatments designed to destroy them.
By helping cancer cells repair this damage, MYC may contribute to treatment resistance and poor outcomes in patients.
“Our study shows that MYC not only helps cancer cells grow, but also helps them resist some treatments designed to kill them,” said lead author Rosalie Sears, Ph.D., the Krista L. Lake Chair in Cancer Research and co-director of the OHSU Brenden Colson Pancreatic Treatment Center.
The study’s lead author, Dr. Gabriel Cohn, conducted the study while working in the Sears lab at OHSU. He is currently a postdoctoral researcher at the University of Würzburg.
“These findings are particularly relevant for aggressive cancers such as pancreatic cancer, where MYC activity is often very high,” he said. “Tumor cells in these cancers experience significant DNA damage and replication stress, yet they survive and continue to grow. Our study suggests that MYC helps these cells cope with that stress by actively promoting DNA repair.”
An unexpected role for MYC in DNA repair
Scientists have been studying MYC for decades because of its key role in cancer. Normally, this protein works in the cell’s nucleus and switches on genes to promote cell growth and metabolism.
New research reveals another function that was not fully understood until now. When DNA is damaged by rapid tumor growth or cancer treatment, a modified version of MYC moves directly to the damaged area and helps recruit proteins needed for repair.
“This is a nontraditional or casual role for MYC,” Sears said. “Rather than controlling gene activity, it physically goes to the site of DNA damage and helps introduce repair proteins.”
This repair process can help cancer cells survive conditions that would kill them.
Why DNA repair is important in cancer treatment
DNA repair is normally essential for healthy cells. However, many treatments work by damaging tumor DNA beyond repair, creating a challenge in cancer treatment.
Both chemotherapy and radiation therapy rely on overwhelming cancer cells with DNA damage. If tumor cells can quickly repair the damage, they may be able to withstand treatment and continue to grow.
“Cancer treatments often rely on overwhelming tumor cells with DNA damage,” Professor Sears said. “If cancer cells are better at repairing that damage, they can withstand treatment and continue to proliferate.”
The researchers found that cells containing an active, modified form of MYC repair DNA damage more efficiently and are more likely to survive stressful conditions, such as exposure to DNA-damaging treatments.
This effect was particularly pronounced in pancreatic cancer, one of the most deadly diseases. Using tumor data and patient-derived pancreatic cancer cells, the research team found that cancers with high MYC activity also showed increased DNA repair activity, which was associated with worse patient outcomes.
This finding may help explain why some tumors resist chemotherapy and radiation therapy. Cancers caused by MYC appear to be able to quickly repair DNA damage caused by treatments, allowing them to withstand treatments that would normally destroy tumor cells.
“In the case of pancreatic cancer, MYC appears to help the tumor withstand extreme stress,” Dr. Sears said. “That stress is caused by rapid growth, poor blood supply, and chemotherapy.”
Targeting MYC in future cancer treatments
The research also supports ongoing efforts at OHSU to develop treatments that target MYC, something scientists once thought impossible to do effectively.
MYC has long been considered “undruggable” because its structure makes it difficult for drugs to safely bind to it without affecting healthy cells. However, researchers believe that MYC’s newly identified role in DNA repair may provide a more precise way to target the protein.
“MYC is one of the two most important oncogenes in all human cancers,” Sears said. “If we can inhibit MYC’s role in DNA repair without blocking all of its functions in healthy cells, we may be able to make cancer cells more amenable to treatment.”
OHSU researchers are already studying a first-in-class MYC inhibitor in a “window of opportunity” trial. In this short-term study, patients with advanced pancreatic cancer will undergo biopsies before and after receiving a drug called OMO-103. The goal is to better understand how blocking MYC changes tumors in real patients.
This research was supported by the National Cancer Institute of the National Institutes of Health (Award Numbers NCI U01CA294548, U01CA224012, U01CA278923, R01CA186241, R01CA287672, R21CA263996), the Department of Defense, Award PA210068, and the Brenden Colson Pancreatic Center. Care, Krista L. Lake Endowed Chair, and Knight Cancer Institute Scholarship Award recipient. The authors also acknowledge technical support from the Flow Cytometry Shared Resource supported by the OHSU Advanced Light Microscopy Core and the OHSU Knight Cancer Institute.
