ARTICLE ABSTRACTTargeting of epigenetic regulators as the chromatin remodeler SWI/SNF is proving to be a promising therapeutic strategy for individualized treatment of cancer patients. Here, we tested whether targeting one of the two mutually exclusive subdomains of the SWI/SNF complex BRM/SMARCA2 can sensitize specifically non–small cell lung carcinoma (NSCLC) cells with mutations in the other subunit BRG1/SMARCA4 toward ionizing radiation (IR). Knockdown of BRM with siRNA or shRNA and its consequences for radiation sensitivity as measured by clonogenic survival and plaque-monolayer control was studied in different NSCLC lines with or without BRG1 mutations and in primary fibroblasts. Furthermore, the effect on double-strand break (DSB) repair markers measured by immunofluorescence staining of 53BP1-, γ-H2AX-, and Rad51-foci was investigated. BRG1-mutated cell lines showed an increased surviving fraction compared with BRG1 proficient cells. Depletion of BRM (i) leads to a decreased proliferation rate and plating efficiency specifically in BRG1-mutated cells, (ii) specifically sensitized BRG1-mutant NSCLC cells toward IR as characterized by a survival reducing factor of 0.63 [95% confidence interval (CI), 0.57–0.69] in the dose range between 2 and 6 Gy, and (iii) decreased the tumor control doses after daily fractionation at 4 Gy in BRG1-mutant NSCLC cell lines A549 and H1299 in minimonolayers by 9.9% ± 1.3% and 13.6% ± 1.8%, respectively. In addition, an increase of residual Rad51-foci at 24 hours after irradiation in BRG1-mutant cells was demonstrated. Therefore, targeting of BRM in combination with radiotherapy is supposed to improve the therapeutic outcome of lung cancer patients harboring BRG1 mutations.The present study shows that the moderate radioresponsiveness of NSCLC cells with BRG1 mutations can be increased upon BRM depletion that is associated with a prolonged Rad51-foci prevalence at DNA DSBs.