Key Takeaways: • Researchers from The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) found a potential new target for therapy that could help patients overcome immunotherapy resistance in small-cell lung cancer (SCLC), one of the most aggressive and difficult-to-treat cancers. • The study was recently published in Nature Communications and led by Triparna Sen, PhD, of the OSUCCC – James. • Researchers say the study has significant implications for developing more effective combination therapies for patients with SCLC. COLUMBUS, Ohio – Findings from a study led by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) support a potential new target for therapy that could help people overcome immunotherapy resistance in small-cell lung cancer (SCLC), one of the most aggressive and difficult-to-treat cancers. The study was recently published in Nature Communications and led by Triparna Sen, PhD, director of the Lung Cancer Preclinical Therapeutics Platform at the OSUCCC – James. SCLCs account for 15% of all lung cancer, with 30,000 new cases diagnosed annually in the United States. “It is known that SCLC responds poorly to immunotherapy and improving patient outcomes remains a major unmet need,” said Sen, also a professor of internal medicine at Ohio State College of Medicine. The study found high PRKDC (a gene in SCLC tumors) expression was linked to poor immunotherapy response. By blocking the protein called DNA-PKcs in the gene, it made the SCLC tumors more visible to the immune system and improved response to immunotherapy in preclinical models. “Our work reveals previously unrecognized mechanistic links, opening new avenues for research and future clinical trials,” said Sen. “These findings have significant implications for developing more effective combination therapies for patients with SCLC and highlight new research directions in tumor immunity and DNA repair.” About the study Researchers investigated the expression of PRKDC in 179,508 human tumor samples across 24 tumor types, including SCLC. SCLC had the highest expression of PRKDC among the 24 types of cancer. Patients with SCLC may not respond as well to immunotherapy when the tumor has high levels of PRKDC, which makes the protein DNA-PKcs. When DNA-PKcs is lowered or blocked, bits of DNA build up in the wrong place inside the cell and can switch on the body’s immune alarm system. This can make the cancer easier for the immune system to recognize and may help immunotherapy work better in lab and animal studies. The new study from the Sen Lab builds on years of work identifying vulnerabilities in the DNA damage response of SCLC. Sen and her team show that targeting key DNA repair pathways not only impairs tumor survival but also activates innate immune signaling, a dual mechanism that reshapes treatment strategies. These findings have direct clinical relevance, supporting ongoing trials and providing a clear rationale for combining DNA damage response inhibitors with immunotherapy. Other study co-authors include Subhamoy Chakraborty from Ohio State and investigators from the Icahn School of Medicine at Mount Sinai, Montefiore Medical Center in New York, Memorial Sloan Kettering Cancer Center, and Nagasaki University Hospital. Media Contact: Mary Ellen Fiorino, MaryEllen.Fiorino@osumc.edu