Scientists shut down cancer DNA repair to overcome drug resistance

Cancer therapies known as PARP inhibitors were designed to exploit weaknesses in DNA repair. While these drugs have been successful against certain tumors, many cancers eventually adapt. By restoring their DNA repair capabilities, they become resistant to treatment and continue growing.

Now, researchers led by Director Kyungjae Myung at the Center for Genomic Integrity within the Institute for Basic Science (IBS), working with Joo-Yong Lee of Chungnam University, have identified a potential way to overcome that resistance. Instead of targeting genetic mutations, the team found a method for destabilizing the machinery cancer cells use to repair DNA.

Targeting DNA Repair Proteins

DNA repair proteins inside cells are constantly being produced and removed to maintain a healthy balance. The researchers discovered that disrupting this balance can leave cancer cells unable to cope with DNA damage.

Using a cell-based screening system designed to identify regulators of replication stress responses, the team identified a small molecule called UNI418. When cancer cells were exposed to UNI418, levels of critical DNA repair proteins, including RAD51 and CHK1, dropped significantly. Without enough of these proteins, the cells struggled to repair damaged DNA.

To understand why this happened, the researchers investigated how the proteins were being 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-corresponding author Professor Joo-Yong Lee stated, "We identified a mechanism in which key DNA repair proteins are actively degraded inside the cell. This provides a new way to regulate homologous recombination beyond genetic mutations."

How UNI418 Triggers Protein Destruction

The team then examined how UNI418 activates this degradation pathway. They found that the molecule interferes with a signaling process involved in inositol phosphate metabolism, leading to lower levels of a molecule known as IP6.

Under normal circumstances, IP6 helps keep Cul4A activity under control. When IP6 levels decline, that restraint is removed, allowing the degradation machinery to become more active.

Once activated, Cul4A works together with an adaptor protein called WDR5 to target DNA repair proteins such as RAD51 for destruction. As these proteins disappear, homologous recombination is effectively shut down.

The result is a condition that resembles DNA repair deficiency, even in cancer cells that had previously regained their repair capabilities. This finding could be especially important for overcoming resistance to PARP inhibitors, which remains a major obstacle in cancer treatment.

Restoring Sensitivity to Cancer Drugs

The researchers tested whether disabling DNA repair in this way could improve the effectiveness of existing therapies. In multiple cell-based studies, UNI418 made cancer cells much more sensitive to PARP inhibitors.

The effect was particularly striking in cancer cells that had already become resistant to PARP inhibitor treatment. In those cases, UNI418 restored the cells' responsiveness to the drugs.

Co-corresponding author Director Kyungjae Myung added, "By weakening the DNA repair system, we can re-sensitize tumors that have become resistant to existing therapies. This suggests a new strategy for expanding the effectiveness of PARP inhibitors."

The team also evaluated the approach in animal models. In tumor xenograft experiments, UNI418 slowed tumor growth, especially when used together with the PARP inhibitor Olaparib. Notably, the benefits were observed even in models designed to mimic treatment-resistant cancers.

These findings suggest that cancer cells remain heavily dependent on DNA repair pathways, even after they have developed resistance to therapy. Disrupting the stability of repair proteins appears to expose a vulnerability that tumors continue to rely on.

A New Link Between Metabolism and Genome Stability

Beyond its potential therapeutic applications, the research uncovered an unexpected connection between cellular metabolism and DNA repair.

By showing that IP6 signaling influences the Cul4A protein degradation pathway, the study reveals a previously unknown mechanism involved in maintaining genome stability. The findings suggest that metabolic processes can directly influence how effectively cells repair DNA.

Co-corresponding author Director Kyungjae Myung remarked, "This study demonstrates that controlling the stability of DNA repair proteins can directly impact cancer cell survival. It also highlights a new therapeutic direction for overcoming drug resistance."

Although UNI418 itself will require additional development and testing, the underlying mechanism offers a promising new framework for future combination therapies. The work suggests that resistant cancers may be made vulnerable once again, not by changing their genes, but by dismantling the repair systems that help them survive.

The study was published in Nature Communications.