Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma

TheKRASoncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. The identification of dependencies borne through common co-occurring mutations are sought to more effectively targetKRAS-mutant lung cancer. Approximately 20% ofKRAS-mutant LUAD carry loss-of-function mutations inKEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2. We demonstrate thatKeap1-deficientKrasG12Dlung tumors arise from a bronchiolar cell-of-origin, lacking pro-tumorigenic macrophages observed in tumors originating from alveolar cells.Keap1loss activates the pentose phosphate pathway, inhibition of which, using 6-AN, abrogated tumor growth. These studies highlight alternative therapeutic approaches to specifically target this unique subset ofKRAS-mutant LUAD cancers.