Researchers develop drugs to disable cancer's DNA repair, boosting radiotherapy effectiveness

Cancer cells have a survival trick that doctors have long struggled against: when radiation or chemotherapy tears apart their DNA, they deploy internal repair crews to stitch the damage back together and keep growing. This resilience is why cancers become resistant to treatment, why doses must climb higher, and why side effects mount. Researchers at Wayne State University and Indiana University have now developed a different approach—not trying to hit cancer harder, but rather disarming its ability to heal itself.

The team, led by Dr. Navnath Gavande at Wayne State and Dr. John Turchi at Indiana University, has created a new class of drugs designed to block a specific protein complex called Ku70/80, which acts as the first responder to broken DNA. When radiation damages cancer cell DNA, Ku70/80 recognizes the break and summons DNA-PK, an enzyme that orchestrates the repair. By targeting Ku70/80 instead of DNA-PK directly, the researchers have found a way to shut down this repair pathway with greater precision and less collateral damage to healthy tissue. The National Cancer Institute has backed this work with a $3.2 million renewed grant, recognizing it as a promising avenue for improving lung cancer treatment.

What makes this approach distinctive is its surgical specificity. Many existing DNA-PK inhibitors work by attacking the enzyme itself, but that broad assault can harm normal cells alongside cancer cells, raising toxicity concerns. The new compounds, called Ku-DNA binding inhibitors or Ku-DBi, work differently. They block the earliest step in the repair process—the moment Ku70/80 binds to damaged DNA—preventing DNA-PK from ever being activated in the first place. Think of it as cutting the power before the repair machinery can even start. In preclinical models, these inhibitors have successfully sensitized cancer cells to radiation, meaning tumors respond to lower doses of treatment.

Turchi, who has spent more than two decades studying DNA repair pathways and their role in cancer resistance, and Gavande have been among the first researchers to pursue this Ku70/80 targeting strategy. Their earlier work identified and optimized small molecules that could enter cells and disrupt the non-homologous end joining pathway—one of cancer's primary DNA repair mechanisms. Now, with renewed funding, the team is moving into the next critical phase: mapping out which types of DNA damage and which cancers are most vulnerable to this approach, and identifying combinations with other therapies that might create what researchers call synthetic lethal interactions—situations where blocking one pathway in a cancer cell becomes lethal when combined with another treatment.

For lung cancer patients, the implications could be substantial. If these drugs can make tumors more responsive to radiotherapy, doctors might be able to deliver effective treatment at lower doses, reducing the radiation-related toxicities that currently limit how aggressively they can treat. The team is also investigating whether Ku-DBi compounds might work against other hard-to-treat solid tumors beyond lung cancer. As Gavande noted, by targeting the earliest step in DNA repair activation, the approach aims to create more selective therapeutic opportunities for cancers that depend heavily on their repair machinery for survival. The next phase of research will test these possibilities and optimize how the compounds move through the body and reach tumors—work that could reshape how radiotherapy is deployed across multiple cancer types.