Binkley MS, Jeon YJ, Nesselbush M, et al. - Because mutations are not normally connected to outcome in localized non–small cell lung cancer (NSCLC), tumor genotyping is not routinely conducted. In this analysis, researchers identified a predictive value of KEAP1 and NFE2L2 mutations in 232 consecutive patients with localized NSCLC for high rates of local recurrence (LR) after radiotherapy but not surgery. KEAP1/NFE2L2 may be major molecular drivers of clinical radioresistance due to the observation that half of LRs were seen in tumors with KEAP1/NFE2L2 mutations. Researchers established that only pathogenic mutations are linked with radioresistance after functionally evaluating KEAP1/NFE2L2 mutations in the radiotherapy cohort. No predictive value was seen in the expression of NFE2L2 target genes for LR, suggesting the utility of tumor genotyping. Finally, it was demonstrated that KEAP1-mutant cells were preferentially radiosensitized by glutaminase inhibition via depletion of glutathione and elevated radiation-induced DNA damage. Per these findings, genotyping for KEAP1/NFE2L2 mutations could aid in the personalization of treatment and offer a possible strategy to overcome radioresistance conferred by these mutations.