Cancer-driving MYC protein also helps tumors repair damaged DNA

A protein best known for driving cancer growth also helps damaged tumor cells survive by repairing their DNA, according to a new study that could influence how some cancers are treated.

Researchers at Oregon Health & Science University found that the protein MYC, which is overactive in most human cancers, plays a direct role in fixing dangerous breaks in DNA. By helping cancer cells survive chemotherapy and other treatments that damage DNA, the protein may contribute to tumor resistance and poor patient outcomes.

The findings, published today in Genes & Development, could open the door to new therapies that make cancer treatments more effective by blocking this repair process.

Our work shows that MYC isn't just helping cancer cells grow - it's also helping them survive some of the very treatments designed to kill them."

Rosalie Sears, Ph.D., senior author, Krista L. Lake Chair in Cancer Research and co-director of the OHSU Brenden-Colson Center for Pancreatic Care

Gabriel Cohn, Ph.D., is first author of the study. Now a postdoctoral researcher at the University of Würzburg, he conducted the research as a student in Sears' lab at OHSU.

"These findings are particularly relevant for aggressive cancers like 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 continue to survive and grow. Our work suggests that MYC helps these cells cope with that stress by actively promoting DNA repair."

MYC is one of the most-studied cancer-related proteins because it is overactive in most human cancers. For decades, scientists have known that MYC acts inside the cell's nucleus to turn genes on, revving up growth and metabolism.

But the new study reveals an unexpected role: When DNA is damaged - whether from the stresses of rapid growth or from chemotherapy - a modified form of MYC moves directly to the damaged DNA and helps recruit repair machinery.

"This is a nontraditional, or non-canonical, role for MYC," Sears said. "Instead of controlling gene activity, it's physically going to sites of DNA damage and helping bring in repair proteins."

That ability allows cancer cells to fix DNA breaks and survive conditions that would otherwise kill them.

DNA damage

While DNA repair is normally a healthy process, it becomes a problem in cancer treatment. Many standard therapies, including chemotherapy and radiation, work by damaging DNA so severely that cancer cells can't survive.

If MYC helps cancer cells repair that damage, treatments can become less effective.

"Cancer therapies often depend on overwhelming tumor cells with DNA damage," Sears said. "If a cancer cell is very good at fixing that damage, it can survive treatment and keep growing."

The study showed that cells with an active, modified form of MYC were better at repairing DNA and more likely to survive under stressful conditions, including exposure to DNA-damaging agents.

The effect was especially evident in pancreatic cancer, one of the deadliest cancers. Using patient-derived pancreatic cancer cells and tumor data, the researchers found that tumors with high MYC activity also showed signs of increased DNA repair and were linked to worse patient outcomes.

The findings help explain why some tumors resist chemotherapy and radiation, both of which work by overwhelming cancer cells with DNA damage. By rapidly repairing that damage, MYC-driven tumors may endure treatment that would otherwise kill them.

"In pancreatic cancer, MYC appears to help tumors tolerate extreme stress," Sears said. "That stress comes from rapid growth, from poor blood supply, and from chemotherapy."

Precise target

Importantly, the study supports ongoing efforts at OHSU to target MYC in people with cancer - something long thought to be impossible.

MYC has often been described as "undruggable," meaning its structure is not amenable to drug binding, and it is hard to block safely without harming normal cells. But Sears and her colleagues believe this newly discovered repair-related function could offer a more precise target.

"MYC is one of the two most important oncogenes in all of human cancer," Sears said. "If we can interfere with MYC's role in DNA repair - without shutting down everything MYC does in healthy cells - we may be able to make cancer cells more vulnerable to treatment."

At OHSU, researchers are already studying a first-in-class MYC inhibitor in a "window of opportunity" trial, a short-term study where people with advanced pancreatic cancer are biopsied before and after taking a drug called OMO-103 with the goal of understanding how blocking MYC affects tumors in real patients.