Cancer cells have a remarkable ability to withstand treatments that damage their DNA. One reason for this is that they rely on sophisticated repair systems that can repair genetic damage that would otherwise kill them. Among the most important of these systems is homologous recombination, a highly precise DNA repair process that relies on proteins such as RAD51 and CHK1.
Cancer treatments known as PARP inhibitors were designed to take advantage of weaknesses in DNA repair. Although these drugs are effective against certain tumors, many cancers eventually adapt. By restoring DNA repair capacity, they become more resistant to treatment and continue to grow.
Now, researchers led by Kyungjae Myung, director of the Center for Genome Integrity at the Institute of Basic Science (IBS), in collaboration with Jooyoung Lee of Chungnam University, have identified a potential way to overcome that resistance. Instead of targeting genetic mutations, the researchers found a way to destabilize the mechanisms cancer cells use to repair their DNA.
Targets DNA repair proteins
DNA repair proteins in cells are constantly produced and removed to maintain a healthy balance. Researchers have found that when this balance is disrupted, cancer cells may be unable to cope with DNA damage.
The research team identified a small molecule called UNI418 using a cell-based screening system designed to identify regulators of the replication stress response. When cancer cells were exposed to UNI418, levels of key DNA repair proteins such as RAD51 and CHK1 were significantly reduced. Without enough of these proteins, cells have a hard time repairing damaged DNA.
To understand why this happened, researchers investigated how the protein is regulated. Their experiments revealed that UNI418 activates a protein disposal pathway called the Cul4A ubiquitin ligase complex. This system marks specific proteins for destruction, effectively dismantling key components of the DNA repair network.
Co-author Professor Joo-Yong Lee said: “We have identified a mechanism by which critical DNA repair proteins are actively degraded within cells. This provides a new way to control homologous recombination beyond genetic mutations.”
How UNI418 causes protein destruction
The researchers then investigated how UNI418 activates this degradation pathway. They found that this molecule interferes with signaling processes involved in inositol phosphate metabolism, leading to decreased levels of a molecule known as IP6.
Under normal circumstances, IP6 helps control Cul4A activity. As the IP6 level decreases, that restriction is lifted, allowing the decomposition mechanism to become more active.
Once activated, Cul4A works with an adapter protein called WDR5 to target and destroy DNA repair proteins such as RAD51. Loss of these proteins effectively halts homologous recombination.
As a result, a state resembling a DNA repair defect develops, even in cancer cells that previously regained repair capacity. This discovery could be particularly important for overcoming resistance to PARP inhibitors, which remains a major obstacle in cancer treatment.
Restore sensitivity to anticancer drugs
The researchers tested whether disabling DNA repair in this way could improve the effectiveness of existing treatments. In multiple cell-based studies, UNI418 made cancer cells much more sensitive to PARP inhibitors.
This effect was particularly pronounced in cancer cells that had already become resistant to PARP inhibitor treatment. In these cases, UNI418 restored cellular responsiveness to the drug.
“By weakening the DNA repair system, we can resensitize tumors that have become resistant to existing treatments. This suggests a new strategy to expand the effectiveness of PARP inhibitors,” added co-author and director Kyungjae Myung.
The research team also evaluated this approach in animal models. In tumor xenograft experiments, UNI418 slowed tumor growth, especially when combined with the PARP inhibitor olaparib. Remarkably, benefits were also observed in models designed to mimic treatment-resistant cancers.
These findings suggest that cancer cells remain highly dependent on DNA repair pathways even after they acquire resistance to treatment. Disrupting the stability of repair proteins appears to expose vulnerabilities on which tumors continue to rely.
A new relationship between metabolism and genome stability
Beyond potential therapeutic applications, this study reveals an unexpected relationship between cellular metabolism and DNA repair.
This study uncovers a previously unknown mechanism involved in maintaining genome stability by showing that IP6 signaling affects the Cul4A proteolytic pathway. The results of this study suggest that metabolic processes can directly influence effective DNA repair in cells.
“This study shows that controlling the stability of DNA repair proteins can directly impact cancer cell survival. It also highlights new therapeutic directions to overcome drug resistance,” said co-corresponding author Kyungjae Myung, director of the study.
Although UNI418 itself requires additional development and testing, the underlying mechanism provides a promising new framework for future combination therapy. This study suggests that resistant cancers may become vulnerable again, not by changing their genes, but by dismantling the repair systems that help cancers survive.
This research nature communications.
