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Newswise — DALLAS – April 30, 2025 – 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 Center researchers. The findings, published in , 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 , Assistant Professor of  and a member of the  at UT Southwestern.

Prior research, including from the  of co-investigator , Professor and Director of the , Professor in , 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.

Other UTSW contributors include first author Jui-Chung Chiang, Ph.D., postdoctoral researcher in the ; John D. Minna, M.D., Director and Professor of the  and co-leader of the Experimental Therapeutics Research Program in the Simmons Cancer Center; Robert D. Timmerman, M.D., Chair and Professor of Radiation Oncology; Anthony Davis, Ph.D., Associate Professor of Radiation Oncology; Zengfu Shang, Ph.D., Assistant Professor of Radiation Oncology; Ling Cai, Ph.D., Assistant Professor in the ; Feng Cai, Ph.D., Assistant Professor in Children’s Medical Center Research Institute at UT Southwestern; and Wei-Min Chen, Ph.D., postdoctoral researcher in Radiation Oncology.

Drs. DeBerardinis, Ling Cai, Davis, Minna, and Timmerman are members of the Simmons Cancer Center. Dr. DeBerardinis is a Howard Hughes Medical Institute Investigator and holds the Eugene McDermott Distinguished Chair for the Study of Human Growth and Development and the Philip O’Bryan Montgomery Jr., M.D., Distinguished Chair in Developmental Biology and is a Sowell Family Scholar in Medical Research.

This research was supported by the Howard Hughes Medical Institute Investigator Program, grants from the National Institutes of Health (R35CA220449, P50CA196516, P50CA070907, and P30CA142543), the Moody Foundation (Robert L. Moody, Sr. Faculty Scholar Award), Jerry and Emy Lou Baldridge, the ASCO Young Investigator Award, the Lung SPORE Career Enhancement Award, a Distinguished Research Award from the President’s Research Council, American Cancer Society Institutional Research Grant (IRG-21-142-16), National Cancer Institute Cancer Center Support Grant (P30CA142543), the National Center for Advancing Translational Sciences of the National Institutes of Health (KL2TR003981 and CTSA-PP-YR1-D-009), Startup Award from UT Southwestern Department of Radiation Oncology, the Once Upon a Time Foundation, and Cancer Prevention and Research Institute of Texas (CPRIT) grant PR180770.

About UT Southwestern Medical Center   

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.