Cancer treatments like radiation and chemotherapy work by doing one main thing: shredding the DNA of cancer cells so they can no longer multiply. However, cancer cells are notoriously resilient and often deploy their own internal “repair crews” to fix treatment-induced damage, continue growing and ultimately become resistant to therapy.
By blocking cancer’s ability to heal itself, researchers at Wayne State University and Indiana University have developed an innovative approach that has the potential to make standard cancer treatments significantly more effective at lower, safer doses.
Backed by a renewed grant from the National Cancer Institute of the National Institutes of Health, the multidisciplinary team of scientists are developing a new class of drugs designed to dismantle cancer’s DNA repair machinery with unprecedented precision, with the goal of improving radiotherapy outcomes for patients with lung cancer.
The $3.2 million grant, “Discovery and development of Ku-targeted small molecule inhibitors: A novel mechanism of DNA-PK inhibition,” is led by Dr. Navnath Gavande, associate professor of pharmaceutical sciences in the Eugene Applebaum College of Pharmacy and Health Sciences at Wayne State University, and Dr. John Turchi, chair of biochemistry, molecular biology and pharmacology at Indiana University School of Medicine. The renewed funding specifically supports the development of Ku-targeted inhibitors as a strategy to enhance lung cancer treatment by improving tumor response to radiotherapy.
Turchi is widely recognized as a pioneer in DNA repair and DNA damage response research, with more than two decades of work dedicated to understanding nucleotide excision repair and non-homologous end joining pathways and their roles in cancer therapy resistance. The laboratories of Gavande and Turchi were among the first to advance the concept of targeting the Ku70/80 DNA-binding complex – a central DNA damage sensor in the NHEJ pathway – as a novel therapeutic strategy for cancer treatment. Building on this foundation, the researchers continue to lead medicinal chemistry optimization and mechanistic studies focused on targeting Ku70/80 for cancer therapy.
Fixing the flaws of current cancer treatments
The research focuses on DNA-dependent protein kinase, or DNA-PK, a critical enzyme that cancer cells use to repair DNA double-strand breaks caused by radiation, chemotherapy and other cellular stresses. DNA-PK has long been considered an attractive therapeutic target in cancer, and several DNA-PK inhibitors are currently being evaluated clinically by pharmaceutical companies. However, many current approaches target the catalytic activity of DNA-PK directly, which can raise concerns about toxicity and effects on normal tissues.
Gavande’s and Turchi’s team are pursuing a different strategy. Instead of targeting DNA-PK directly, their compounds, called Ku-DNA binding inhibitors (Ku-DBi) are designed to block Ku70/80, the DNA damage sensor that recognizes broken DNA ends and recruits DNA-PK to initiate repair. Without Ku binding to damaged DNA, DNA-PK cannot be properly activated. In this way, Ku-DBi’s act like a precision “off-switch” for a key DNA repair pathway that cancer cells depend on for treatment resistance.
A new weapon against hard-to-treat solid tumors
During the initial phase of funding, the team discovered and optimized Ku-targeted small molecules that enter cells, inhibit DNA-PK activation, disrupt NHEJ-mediated DNA repair, and sensitize cancer cells to radiation and radiomimetic agents in preclinical models. With renewed NIH support, the investigators will move the program into its next critical phase: defining the DNA damage contexts and cancer vulnerabilities where Ku-DBi’s may have the greatest therapeutic impact.
In this next phase of our research, we will investigate various DNA double-strand break repair contexts to identify novel therapeutic combinations with Ku-DBi’s. We will also work to discover where Ku-DBi’s can create new synthetic lethal interactions in cancers that are currently difficult to target with precision therapies, while continuing our medicinal chemistry efforts to optimize in vivo activity and delivery of these compounds.”
Dr. Navnath Gavande, associate professor of pharmaceutical sciences, Eugene Applebaum College of Pharmacy and Health Sciences at Wayne State University
Working on this project has been an exciting opportunity to contribute to the development of first-in-class Ku70/80 DNA-binding inhibitors and to better understand how targeting DNA repair can improve radiotherapy for lung cancer and other difficult-to-treat tumors,” said Dr. Narva Kushwaha, a postdoctoral researcher in Gavande’s laboratory.
“Our innovative approach of targeting the structure-specific DNA-binding protein Ku aims to significantly enhance our understanding of the DNA damage response and mechanisms of DNA repair,” said Gavande. “By targeting the earliest step in DNA-PK activation, we hope to create more selective therapeutic opportunities for cancers that depend heavily on DNA repair for survival.”
Why it matters
For lung cancer patients, the ability to sensitize tumors to radiotherapy could help improve tumor control while reducing the dose-related toxicities that limit treatment. The development of these new chemical entities represents a major leap forward in precision medicine, offering new hope for safer, more effective treatments across a wide range of human cancers.
Research reported in this press release was supported by the National Cancer Institute of the National Institutes of Health under award number R01CA247370. The content of this press release is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
