Researchers have discovered a way to dismantle the DNA repair systems that allow cancer cells to survive treatment and develop drug resistance, potentially reopening a path for therapies that had stopped working.
The immune system's ability to fight cancer has long been hampered by a simple fact: cancer cells are extremely good at fixing the damage that treatment inflicts on them. When chemotherapy or other drugs tear apart a cancer cell's DNA, sophisticated repair machinery kicks in and patches the damage before it can kill the cell. One of the most effective repair processes is called homologous recombination, which relies on proteins like RAD51 and CHK1 to restore genetic integrity.
A class of cancer drugs called PARP inhibitors was specifically designed to attack this weakness by blocking DNA repair. These drugs have worked well against certain tumors, but many cancers eventually develop resistance by restoring their repair capabilities and continuing to grow unchecked.
Now a team led by Kyungjae Myung at the Center for Genomic Integrity within the Institute for Basic Science, working with Joo-Yong Lee of Chungnam University, has found a way to turn off this repair system without waiting for genetic changes to occur. Rather than targeting mutations, the researchers identified a method to destabilize the actual proteins that perform the repairs.
The team screened thousands of small molecules to find ones that could disrupt how cancer cells produce and maintain their repair proteins. They identified a compound called UNI418 that dramatically reduces levels of critical DNA repair proteins inside cancer cells. When exposed to UNI418, cells lose the ability to fix DNA damage and become vulnerable again to treatment.
The mechanism turned out to involve an unexpected link between cellular metabolism and genome stability. UNI418 interferes with a signaling process that normally keeps repair proteins stable. Specifically, the molecule disrupts inositol phosphate metabolism, causing levels of a signaling molecule called IP6 to drop. Without sufficient IP6, a protein degradation system called Cul4A ubiquitin ligase becomes hyperactive and marks repair proteins for destruction.
"We identified a mechanism in which key DNA repair proteins are actively degraded inside the cell," Lee said. "This provides a new way to regulate homologous recombination beyond genetic mutations."
When the researchers tested this approach in cancer cells that had already become resistant to PARP inhibitors, the results were striking. UNI418 restored the cells' sensitivity to the drugs, making them vulnerable to treatment once again. The effect held up in animal models as well, where tumor growth slowed when UNI418 was combined with the PARP inhibitor Olaparib, even in cancers engineered to mimic treatment-resistant tumors.
The finding suggests that even after cancer cells acquire resistance, they remain dependent on DNA repair pathways to survive. By destabilizing the proteins that perform these repairs rather than targeting genetic mutations, researchers may have found a way to overcome a major barrier in cancer therapy.
Though UNI418 itself will require extensive development and testing before clinical use, the underlying principle offers a new framework for combination treatments. Instead of accepting that resistant cancers have found ways around existing drugs, this approach suggests those cancers can be made vulnerable again by dismantling the machinery they depend on to survive.
The research was published in Nature Communications.
Author Jessica Williams: "This work cracks open a fundamental survival strategy cancer cells use to outlast treatment, and it does so by exploiting metabolism rather than genetics, which could mean fewer opportunities for tumors to adapt."
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