Scientists have uncovered an unexpected reason why some cancers return after initially responding to treatment.
One of the toughest obstacles in modern cancer treatment is drug resistance. Tumors often respond at first, only to return later in a form that no longer responds to therapy. Scientists still do not fully understand the molecular processes that allow this to happen, which makes it harder to design treatments that can prevent resistance in the first place.
Researchers at the University of California, San Diego have now identified an unexpected survival strategy. They found that cancer cells can recover and grow again after targeted therapy by co-opting an enzyme that is normally activated only when a cell is dying.
“This flips our understanding of cancer cell death on its head,” said senior author Matthew J. Hangauer, Ph.D., assistant professor of dermatology at UC San Diego School of Medicine and Moores Cancer Center member. “Cancer cells which survive initial drug treatment experience sublethal cell death signaling which, instead of killing the cell, actually helps the cancer regrow. If we block this death signaling within these surviving cells, we can potentially stop tumors from relapsing during therapy.”
A global problem driven by treatment resistance
Cancer accounts for roughly one in six deaths worldwide. In many cases, patients initially respond well to treatment, but the cancer later adapts and returns. Traditionally, this resistance develops over months or years through genetic mutations, similar to how bacteria gradually become resistant to antibiotics. Once these mutations arise, treatment options can be limited and difficult to manage with existing drug combinations.
The newly identified process operates much earlier and does not depend on genetic mutations. Because it occurs in the earliest phase of resistance, it may offer a new opportunity to intervene before long term genetic changes take hold.
“Most research on resistance focuses on genetic mutations,” said first author August F. Williams, Ph.D., a postdoctoral fellow in the Hangauer lab at UC San Diego. “Our work shows that non-genetic regrowth mechanisms can come into play much earlier, and they may be targetable with drugs. This approach could help patients stay in remission longer and reduce the risk of recurrence.”
Persister cells and low level death enzyme activity
In the new study, the researchers found:
- In models of melanoma, lung and breast cancers, a subset of “persister” cells that survive treatment showed ongoing low level activation of a protein involved in normal cell death that breaks apart DNA, known as DNA fragmentation factor B (DFFB).
- The amount of DFFB activity was not strong enough to kill the cells, but it was sufficient to disrupt how the cells respond to signals that would normally slow their growth.
- When the researchers removed this protein, persister cells remained dormant and did not regrow during treatment.
- DFFB is not essential for normal cells, but it is necessary for the regrowth of cancer persister cells. This makes it an appealing target for combination therapies designed to prolong the benefits of targeted treatment.
The findings were published in Nature Cell Biology.
Reference: “DNA fragmentation factor B suppresses interferon to enable cancer persister cell regrowth” by August F. Williams, David A. G. Gervasio, Claire E. Turkal, Anna E. Stuhlfire, Michael X. Wang, Brandon E. Mauch, Rhea Plawat, Ariel H. Nguyen, Michelle H. Paw, Mehrshad Hairani, Cooper P. Lathrop, Sophie H. Harris, Jennifer L. Page and Matthew J. Hangauer, 17 November 2025, Nature Cell Biology.
DOI: 10.1038/s41556-025-01810-x
The research was supported in part by funding from the Department of Defense, the National Institutes of Health and the American Cancer Society. Hangauer is a cofounder, consultant and research funding recipient of BridgeBio subsidiary Ferro Therapeutics.
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