One of the reasons cancer cells are so dangerous is their ability to shift between distinct “cell states,” a trick that helps them spread, survive treatment, and come back even after therapy initially works.
Researchers from Duke University School of Medicine have discovered a new vulnerability that appears during the brief moments when cancer cells switch from one state to another. They also identified a way to exploit this weakness, opening a potential new path for cancer treatment.
“We discovered a way to kill cancer cells that are in transition between these states,” said senior author Lee Zou, PhD. “In the past, people have tried to target cancer cells in stable states, but this can be very challenging. We identified a vulnerability associated with cell-state transitions and developed a strategy to target it.”
Zou is the George Barth Geller Distinguished Professor and Chair of the Department of Pharmacology and Cancer Biology.
The study appears in Journal of Clinical Investigation.
Targeting a stress-response protein
Cancer cells rely on a DNA damage repair protein called ATR to survive the stress of switching identities.
In a mouse model, the team found that blocking ATR at the right moment slowed the growth of the tumor and significantly reduced the cancer’s ability to spread.
What happens during these transitions?
When cancer cells shift from an “epithelial” identity to a “mesenchymal” one — a change that helps them become more mobile and invasive — the researchers observed multiple signs of genomic stress:
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Harmful structures called R-loops formed when RNA bound to DNA in the wrong way.
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Transcription replication conflicts developed when the cell’s gene-reading machinery collided with its DNA-copying machinery.
These problems created DNA damage that cancer cells must repair to survive. By inhibiting ATR, the researchers were able to exploit this temporary window of vulnerability.
Looking ahead, Zou said his team is now applying this model to other types of cell-state transitions in cancer cells to see whether the same temporary weaknesses appear beyond the epithelial-to-mesenchymal shift. These explorations could inform development of existing ATR inhibitors, which are now in clinical trials.
Collaboration and funding
The work was a collaboration with scientists at Harvard Medical School and the Howard Hughes Medical Institute.
Other Duke authors: Ajinkya Kawale, PhD, senior research associate, and Xiaojuan Ran, PhD, postdoctoral associate.
Funding: The National Institutes of Health, the Canadian Institutes of Health, and the Rivkin Center.