Cancer treatments such as radiation and chemotherapy work primarily by shredding the DNA of cancer cells so that they can no longer reproduce. However, cancer cells are known to be resilient, often deploying their own internal “repair squads” to repair the damage caused by treatment, continue to proliferate, and eventually become resistant to treatment.
Researchers at Wayne State University and Indiana University have developed an innovative approach that has the potential to significantly increase the effectiveness of standard cancer treatments at lower doses and safely by inhibiting cancer’s ability to heal itself.
With support from a new grant from the National Institutes of Health’s National Cancer Institute, an interdisciplinary team of scientists is developing a new class of drugs designed to disrupt cancer’s DNA repair mechanisms with unprecedented precision, with the goal of improving radiation treatment outcomes for lung cancer patients.
The $3.2 million grant, “Discovery and Development of Ku-Targeting Small Molecule Inhibitors: Novel Mechanisms of DNA-PK Inhibition,” is led by Navnath Gabande, Ph.D., associate professor of pharmacy in Wayne State University’s Eugene Applebaum School of Pharmacy and Health Sciences, and John Turki, Ph.D., chair of the Department of Biochemistry, Molecular Biology, and Pharmacology at Indiana University School of Medicine. New funding will support the development of inhibitors specifically targeting Ku 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, having dedicated more than 20 years of research to understanding nucleotide excision repair and nonhomologous end-joining pathways and their role in cancer treatment resistance. Gavande and Turchi’s lab was one of 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 new therapeutic strategy for cancer treatment. Building on this foundation, researchers continue to lead medicinal chemistry optimization and mechanistic studies focused on targeting Ku70/80 in cancer therapy.
Correcting flaws in current cancer treatments
This research focuses on DNA-dependent protein kinase (DNA-PK), a key enzyme used by cancer cells 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 under clinical evaluation by pharmaceutical companies. However, many current approaches directly target the catalytic activity of DNA-PK, which may raise concerns regarding toxicity and effects on normal tissues.
Gabande and Turki’s team are pursuing a different strategy. The compound, called Ku-DNA Binding Inhibitor (Ku-DBi), is designed to block Ku70/80, a DNA damage sensor that recognizes broken DNA ends and recruits DNA-PK to initiate repair, rather than directly targeting DNA-PK. Without Ku binding to damaged DNA, DNA-PK cannot be properly activated. In this way, Ku-DBi acts like a precise “off switch” for critical DNA repair pathways that cancer cells rely on to gain treatment resistance.
A new weapon against hard-to-treat solid tumors
In the early stages of funding, the team discovered and optimized a Ku-targeted small molecule that enters cells, inhibits DNA-PK activation, disrupts NHEJ-mediated DNA repair, and sensitizes cancer cells to radiation and radiomimetics in preclinical models. With new support from NIH, the researchers will take the program to the next critical step: defining the DNA damage landscape and cancer vulnerability in which Ku-DBi may have the greatest therapeutic effect.
The next stage of our research will investigate different DNA double-strand break repair situations to identify new therapeutic combinations with Ku-DBi. We will also work to discover where Ku-DBi can create new synthetic lethal interactions in cancers that are currently difficult to target with precision therapies, while continuing medicinal chemistry efforts to optimize the in vivo activity and delivery of these compounds. ”
Dr. Navnath Gavande, Associate Professor of Pharmacy, Wayne State University Eugene Applebaum College of Pharmacy and Health Sciences
“Working on this project was an exciting opportunity to contribute to the development of a first-in-class Ku70/80 DNA binding inhibitor and to better understand how targeting DNA repair can improve radiation therapy for lung cancer and other difficult-to-treat tumors,” said Narva Kushwaha, Ph.D., a postdoctoral fellow in the Gabande lab.
“Our innovative approach, which targets the structure-specific DNA-binding protein Ku, aims to significantly increase our understanding of the mechanisms of DNA damage response and DNA repair,” said Gabande. “By targeting the earliest stages of DNA-PK activation, we hope to create more selective treatment opportunities for cancers that rely heavily on DNA repair for survival.”
why is it important
For lung cancer patients, the ability to increase tumor sensitivity to radiotherapy could help improve tumor control while reducing treatment-limiting dose-related toxicities. The development of these new chemicals represents a major advance in precision medicine and offers new hope for safer and more effective treatments for 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 contents of this press release are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
