Clinicopathological, microenvironmental and genetic determinants of molecular subtypes in KEAP1/NRF2‐mutant lung cancer

Somatic KEAP1‐NRF2 pathway alterations are frequently detected in both lung adenocarcinomas and squamous cell carcinomas. However, the biological characteristics and molecular subtypes of KEAP1/NRF2‐mutant lung cancer remain largely undefined. Here, we performed a stepwise, integrative analytic and experimental interrogation of primary tumors and cancer cell lines harboring KEAP1 or NFE2L2 (encoding NRF2) gene mutations. First, we discovered that KEAP1/NRF2‐mutant lung cancer presented APOBEC‐mediated mutational signatures, impaired tumor angiogenesis, elevated hypoxic stress and deficient immune‐cell infiltrates. Second, gene expression‐based subtyping revealed three molecular subsets of KEAP1/NRF2‐mutant lung adenocarcinomas and two molecular subsets of KEAP1/NRF2‐mutant lung squamous cell carcinomas, each associated with distinguishing genetic, differentiation, immunological and clinicopathological properties. Third, single‐sample prediction allowed for de novo identification of KEAP1/NRF2‐active tumors within KEAP1/NRF2‐wild‐type samples. Our data demonstrate that KEAP1/NRF2‐mutant lung cancer is a microenvironmentally distinct, biologically heterogeneous, and clinically underestimated disease. These new pathological and molecular insights may accelerate the development of efficacious therapeutic strategies against human malignancies featured by KEAP1‐NRF2 pathway activation.