Scientists engineer next-generation cancer treatments by disabling tumor DNA repair

DETROIT — Traditional cancer therapies such as radiation and chemotherapy attack tumor cells by damaging their DNA, but many cancers survive by invoking efficient internal repair systems. A key obstacle in oncology is that these repair pathways can restore broken DNA and help cancer cells evolve resistance to treatment. Now, researchers at Wayne State University and Indiana University report a strategy that aims to disable a central DNA repair sensor with greater precision than existing DNA-PK inhibitors.

The work is supported by a renewed $3.2 million grant from the National Cancer Institute (National Institutes of Health). The project is building a new drug class intended to weaken cancer’s DNA double-strand break repair while enabling standard treatments to work at lower doses. The focus is lung cancer, where improved responses to radiotherapy could translate into better tumor control and reduced dose-related toxicity.

Led by Dr. Navnath Gavande (Wayne State University) and Dr. John Turchi (Indiana University School of Medicine), the team targets the Ku70/80 complex that sits at the start of the non-homologous end joining (NHEJ) pathway. In NHEJ, Ku recognizes DNA ends and recruits DNA-dependent protein kinase (DNA-PK) to initiate repair. By preventing Ku from binding damaged DNA, the researchers aim to shut down DNA-PK activation at its earliest functional step.

Unlike therapies that inhibit DNA-PK enzymatic activity directly, the Ku-targeted approach is designed as a “precision off-switch.” This structural strategy is intended to reduce unwanted effects on normal tissues by focusing on the DNA-binding event required for pathway activation. The idea is to block the recognition of broken DNA ends rather than merely interrupt the catalytic machinery downstream.

During the first funding phase, the group discovered and optimized small molecules that can enter cells, interfere with DNA-PK activation, disrupt NHEJ-mediated repair, and sensitize cancer cells to radiation and radiomimetic agents in preclinical models. With the renewed NIH support, the researchers plan to define which DNA damage contexts and tumor vulnerabilities yield the strongest therapeutic windows for Ku-binding inhibitors.

A central goal in the next stage is identifying combination opportunities. The team will search for DNA double-strand break repair settings in which Ku-DBi compounds create synthetic lethal interactions—situations where cancer cells die when two pathways are effectively compromised, but normal cells tolerate the disruption better.

“Our next phase will investigate various DNA double-strand break repair contexts to identify novel therapeutic combinations with Ku-DBi’s,” Gavande said. Alongside these biological studies, the program will continue medicinal chemistry optimization to improve in vivo potency and delivery.

The ultimate target is a first-in-class Ku70/80 DNA-binding inhibitor platform that enhances radiotherapy effectiveness by undermining DNA repair dependence. If successful, the approach could offer a more selective route to radiosensitization across hard-to-treat solid tumors beyond lung cancer.