An FDA-designated orphan drug that can target a key vulnerability in lung cancer shows promise in improving the efficacy of radiation treatments in preclinical models, according to a study by UT Southwestern Medical Centre researchers. The findings, published in Science Advances, suggest a new way to enhance the response to radiotherapy by inhibiting DNA repair in lung cancer cells.

“This study was motivated by challenges faced by millions of cancer patients undergoing radiation therapy, where treatment-related toxicities limit both curative potential and the patient’s quality of life,” said principal investigator Yuanyuan Zhang, M.D., Ph.D., Assistant Professor of Radiation Oncology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Prior research, including from the laboratory of co-investigator Ralph J. DeBerardinis, M.D., Ph.D., Professor and Director of the Eugene McDermott Center for Human Growth and Development, Professor in Children’s Medical Center Research Institute at UT Southwestern, and co-leader of the Cellular Networks in Cancer Research Program in the Simmons Cancer Center, has demonstrated that altered metabolic pathways in lung cancer cells allow them to survive, grow, and spread. But the role of metabolism in enhancing radiation efficacy has not been thoroughly explored.

To identify metabolic pathways that allow cancer cells to survive radiation therapy, researchers conducted an unbiased CRISPR screen that identified lipoylation, a crucial process for mitochondrial enzyme function. Further investigation linked lipoylation deficiency to impaired DNA repair in cancer cells.

Lipoylation can be inhibited by the drug CPI-613, also known as devimistat, which received orphan drug status from the Food and Drug Administration (FDA). Orphan drugs are used to treat rare conditions and come with certain incentives to encourage their development, given their small patient population. However, CPI-613 has not been found to improve outcomes on its own among patients with non-small cell lung cancer or in combination with surgical approaches in pancreatic cancer. In this study, researchers paired the drug with radiation to measure its effects in cancer cell lines and in mouse models of lung cancer.

“This study demonstrates for the first time that inhibiting lipoylation enhances lung cancer cells’ response to radiotherapy, offering a clinically translatable strategy using a clinically tested drug,” Dr. Zhang said.