Cancer’s most notorious growth protein may also be helping tumors survive chemotherapy.
A protein already known for fueling cancer growth may have another troubling ability: helping damaged tumor cells repair their DNA and survive treatments designed to destroy them.
Researchers at Oregon Health & Science University (OHSU) report that MYC, a protein that is overactive in most human cancers, directly participates in repairing dangerous DNA breaks. By helping cancer cells recover from chemotherapy and other DNA-damaging therapies, MYC may contribute to treatment resistance and poorer outcomes for patients.
The study, published in Genes & Development, points to a potential new strategy for cancer treatment. If scientists can block this DNA repair function, they may be able to make tumors more vulnerable to existing therapies.
“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 senior author Rosalie Sears, Ph.D., Krista L. Lake Chair in Cancer Research and co-director of the OHSU Brenden-Colson Center for Pancreatic Care.
The study’s first author, Gabriel Cohn, Ph.D., conducted the research as a student in Sears’ laboratory at OHSU and is now a postdoctoral researcher at the University of Würzburg.
“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’s Unexpected Role in DNA Repair
MYC has been studied extensively because of its central role in cancer. Scientists have long understood that it works inside a cell’s nucleus, activating genes that drive growth and metabolism.
The new research uncovered a very different function.
When DNA becomes damaged, whether from the strain of rapid tumor growth or from chemotherapy, a modified form of MYC travels directly to the damaged areas of DNA. Once there, it helps recruit the cellular machinery needed to carry out repairs.
“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.”
As a result, cancer cells can repair broken DNA and continue surviving under conditions that might otherwise kill them.
Why DNA Repair Can Undermine Cancer Treatment
DNA repair is normally an essential process that protects healthy cells. In cancer treatment, however, it can become a major obstacle.
Many common therapies, including chemotherapy and radiation, work by inflicting so much DNA damage that cancer cells can no longer survive. If tumors are able to repair that damage efficiently, treatment becomes 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 researchers found that cells containing an active, modified form of MYC repaired DNA more effectively and were more likely to survive stressful conditions, including exposure to DNA-damaging agents.
The effect was particularly striking in pancreatic cancer, one of the deadliest forms of the disease. Analyses of patient-derived pancreatic cancer cells and tumor data revealed that tumors with high MYC activity showed increased DNA repair activity and were associated with poorer patient outcomes.
These findings may help explain why some tumors are able to withstand chemotherapy and radiation. By rapidly repairing treatment-induced DNA damage, MYC-driven cancers may survive therapies that would otherwise eliminate 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.”
A Potential New Target for Cancer Therapy
The findings also strengthen ongoing efforts at OHSU to develop ways to target MYC in cancer patients, an objective that for years was considered out of reach.
MYC has frequently been labeled “undruggable” because its structure makes it difficult for drugs to bind to it, and because blocking it can risk harming normal cells. However, researchers believe MYC’s newly discovered role in DNA repair could provide a more precise therapeutic 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.”
OHSU researchers are already investigating this possibility through a “window of opportunity” trial involving a first-in-class MYC inhibitor called OMO-103. In the short-term study, patients with advanced pancreatic cancer undergo biopsies before and after receiving the drug, allowing researchers to examine how blocking MYC affects tumors in real patients.
Reference: “MYC serine 62 phosphorylation promotes its association with DNA double-strand breaks to facilitate repair and cell survival under genotoxic stress” by Gabriel M. Cohn, Colin J. Daniel, Jennifer R. Eng, Alannah S. MacDonald, Jonathan St-Germain, Nadja M. Pieper, Toshita Kannan, Xiao-Xin Sun, Carl Pelz, Ariffin Ali, Koei Chin, Alexander Smith, Charles D. Lopez, Jonathan R. Brody, Brian Raught, Linda Z. Penn, Martin Eilers, Mu-shui Dai and Rosalie C. Sears, 15 May 2026, Genes.
DOI: 10.1101/gad.352832.125
This work was supported by the National Cancer Institute, of the National Institutes of Health, under award numbers NCI U01CA294548, U01CA224012, U01CA278923, R01CA186241, R01CA287672, R21CA263996, the Department of Defense, award PA210068, the Brenden-Colson Center for Pancreatic Care, the Krista L. Lake Endowed Chair and the Knight Cancer Institute stipend award. The authors acknowledge expert technical assistance by the OHSU Advanced Light Microscopy Core and the Flow Cytometry Shared Resource supported by the OHSU Knight Cancer Institute.
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