Abstract We searched for gene expression prognostic markers with bimodal distribution in lung adenocarcinoma (LUAD) that might help specify molecular subtypes and identified a highly consistent biomarker KYNU, an enzyme in the pathway that converts tryptophan to nicotinamide adenine dinucleotide (NAD+). KYNU performed better in predicting LUAD outcomes than genes in related pathways. High KYNU expression is particularly observed in tumors with mutations in the tumor suppressor genes KEAP1 and STK11, but not in the oncogene KRAS. From clinical data of LUAD, we found more frequent co-mutation of KEAP1 and STK11 than KRAS with either KEAP1 or STK11. Tumors with mutations in both KEAP1 and STK11 had poorer outcomes than tumors with mutations in neither or only one of these genes, regardless of KRAS status. Importantly, KYNU expression associated with poor outcomes regardless of KEAP1/STK11 status and other covariates. We also assessed clinical features associated with KEAP1/STK11 mutations with AACR GENIE data. By examining co-expression of KYNU with other genes, we determined that high KYNU expression had low expression of gene sets related to macrophages. Citation Format: Ling Cai, Thomas J. Rogers, Huiyu Li, Jiyeon Kim, Yang Xie, Guanghua Xiao, John Minna, Ralph J. DeBerardinis. KYNU expression is a prognostic factor in KEAP1/STK11 co-mutated lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 871.