Scientists discover why some cancers survive chemotherapy

Cancer’s favorite growth protein may also be secretly helping tumors survive chemotherapy.

Scientists have discovered that a powerful cancer-linked protein does more than fuel tumor growth. It also helps cancer cells survive by repairing damaged DNA, a finding that could eventually improve treatments for some of the deadliest cancers.

The study, published in Genes & Development, focused on MYC, a protein that is abnormally active in most human cancers. Researchers at Oregon Health & Science University (OHSU) found that MYC directly helps fix 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 poorer outcomes for patients.

"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.

Gabriel Cohn, Ph.D., the study's first author, carried out the research while working in Sears' lab at OHSU. He 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

Scientists have studied MYC for decades because of its major role in cancer. Normally, the protein works inside a cell's nucleus, switching genes on to drive cell growth and metabolism.

The new research uncovered another function that had not been fully understood before. When DNA becomes damaged, whether from rapid tumor growth or from cancer treatments, a modified version of MYC moves directly to the damaged area and helps gather the proteins needed for repair.

"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 can help cancer cells survive conditions that would otherwise kill them.

Why DNA Repair Matters in Cancer Treatment

DNA repair is normally essential for healthy cells. However, it creates a challenge in cancer therapy because many treatments work by damaging tumor DNA beyond repair.

Chemotherapy and radiation both rely on overwhelming cancer cells with DNA damage. If tumor cells can quickly repair that damage, they may survive treatment and continue growing.

"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 the active, modified form of MYC repaired DNA damage more efficiently and were more likely to survive stressful conditions, including exposure to DNA-damaging treatments.

The effect was especially noticeable in pancreatic cancer, one of the deadliest forms of the disease. Using tumor data and pancreatic cancer cells derived from patients, the team found that cancers with high MYC activity also showed increased DNA repair activity and were associated with worse patient outcomes.

The findings may help explain why some tumors resist chemotherapy and radiation. MYC-driven cancers appear able to rapidly repair the DNA damage caused by treatment, allowing them to endure therapies that would normally destroy tumor cells.

"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."

Targeting MYC in Future Cancer Therapies

The research also supports ongoing efforts at OHSU to develop treatments that target MYC, something scientists once believed could not be done effectively.

MYC has long been labeled "undruggable" because its structure makes it difficult for drugs to bind to it safely without affecting healthy cells. However, the researchers believe 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 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 already investigating a first-in-class MYC inhibitor in a "window of opportunity" trial. In the short-term study, patients with advanced pancreatic cancer 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.

The study 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 also acknowledged technical support from the OHSU Advanced Light Microscopy Core and the Flow Cytometry Shared Resource supported by the OHSU Knight Cancer Institute.