Abstract 1476: Enhancing radiation sensitivity in CHD5 dysregulated NSCLC by targeting NHEJ repair pathway

Abstract Lung cancer, particularly non-small cell lung cancer (NSCLC), is a leading cause of cancer deaths, with 5-year survival rates decreasing from 65% for localized cases to 9% for distant metastases. Radiation therapy's effectiveness is often limited due to the upregulation of DNA repair pathways like non-homologous end joining (NHEJ), which helps cancer cells survive DNA damage from radiation. Chromatin remodeling plays a crucial role in regulating DNA repair pathways, including NHEJ. We have identified CHD5, a tumor suppressor involved in chromatin remodeling, as a regulator of DNA double-strand break repair pathway choice. DNA reporter assays show that CHD5 promotes homologous recombination (HR), and its depletion enhances NHEJ activity. Analysis of The Cancer Genome Atlas (TCGA) reveals that CHD5 is downregulated in lung adenocarcinoma (LUAD) patients. This suggests that NSCLC cells may rely more on NHEJ due to reduced CHD5 function. Therefore, targeting CHD5-dysregulated NSCLC cells with NHEJ inhibitors could increase their sensitivity to radiation therapy. Our data indicate that overexpressing CHD5 in H460 NSCLC cells reduces levels of phosphorylated and total DNA-dependent protein kinase catalytic subunits (DNA-PKcs), essential components of the NHEJ pathway. This suggests that CHD5 negatively regulates NHEJ. Cell viability assays confirm that CHD5 depletion via siRNA in H460 NSCLC cells sensitizes them to ionizing radiation (IR) when combined with the DNA-PK inhibitor Nu7441, leading to increased cell death. In summary, CHD5 regulates NHEJ in NSCLC, and its depletion makes cancer cells more dependent on NHEJ for DNA repair. Targeting NHEJ in CHD5-deficient NSCLC cells offers a promising therapeutic strategy for enhancing the efficacy of radiation therapy in NSCLC. Citation Format: Seohyun Kim, Sandip K. Rath, Gina Cutlip, David S. Yu. Enhancing radiation sensitivity in CHD5 dysregulated NSCLC by targeting NHEJ repair pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1476.