MYC protein found to repair DNA in cancer cells

A protein long associated with fuelling cancer growth has now been found to help damaged tumour cells survive by repairing their DNA, according to a new study that could change the way some cancers are treated.

Researchers at Oregon Health & Science University discovered that the protein MYC, which is overactive in most human cancers, plays a direct role in repairing dangerous breaks in DNA. The findings suggest the protein may help tumours resist chemotherapy and radiation by enabling cancer cells to recover from treatment-induced damage.

The study could help to inform new therapies that block this repair process and make cancer treatments more effective.

MYC found to play unexpected role

For decades, scientists have understood MYC as a protein that operates inside a cell’s nucleus, switching genes on and accelerating growth and metabolism. However, the new research uncovered what scientists describe as a ’non-canonical’ function.

“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,” said Dr Rosalie Sears, Krista Lake, Chair in Cancer Research and Co-director of the OHSU Brenden-Colson Center for Pancreatic Care.

The research showed that when DNA is damaged, either through rapid tumour growth or exposure to 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 repair process allows cancer cells to recover from DNA breaks that would otherwise destroy them.

Implications for pancreatic cancer

Dr Gabriel Cohn, first author of the study and now a postdoctoral researcher at the University of Würzburg, carried out the work while studying in Sears’ laboratory at OHSU.

“These findings are particularly relevant for aggressive cancers like pancreatic cancer, where MYC activity is often very high,” he said. “Tumour 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.”

Using patient-derived pancreatic cancer cells and tumour data, researchers found that cancers with high MYC activity also showed evidence of increased DNA repair and were linked to poorer patient outcomes.

The effect was especially significant in pancreatic cancer, one of the deadliest forms of the disease. Researchers believe the findings help explain why some tumours are able to survive treatments designed to overwhelm cancer cells with DNA damage.

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

“In pancreatic cancer, MYC appears to help tumours tolerate extreme stress,” she added. “That stress comes from rapid growth, from poor blood supply and from chemotherapy.”

Hope for new treatments

The findings also support ongoing efforts to target MYC directly in cancer patients, despite the protein long being considered ’undruggable’ because of the difficulty of blocking it without harming healthy cells.

“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.”

Researchers at OHSU are now investigating a first-in-class MYC inhibitor in a ’window of opportunity’ trial involving patients with advanced pancreatic cancer. The study examines tumour samples before and after treatment with the drug OMO-103 to better understand how blocking MYC affects cancer cells in patients.