Integrative omics analysis identifies subtypes with therapeutic implications in lung adenocarcinoma harboring KEAP1/NFE2L2

Abstract

Backgrounds: Lung adenocarcinoma is one of the most common malignant tumors, in which KEAP1-NFE2L2 pathway is altered frequently. The biological features and intrinsic heterogeneities of KEAP1/NFE2L2-mutant lung adenocarcinoma remain unclear. Methods: Multiplatform data from The Cancer Genome Atlas (TCGA) were adopted to identify two subtypes of lung adenocarcinoma harboring KEAP1/NFE2L2 mutations. Bioinformatics analyses, regarding immune microenvironment, methylation level and mutational signature, were performed to characterize intrinsic heterogeneities. Meanwhile, initial results were also validated by using common lung adenocarcinoma cell lines, which revealed consistent features of KEAP1/NFE2L2-mutant subtypes. Furthermore, cell line samples were adopted for drug sensitivity screening based on public datasets. Results: Two mutant subtypes (P1 and P2) of patients were identified in TCGA. P2 patients had significantly heavier smoking levels and worse survival compared with P1 patients. The P2 subset was characterized by active immune microenvironment and more smoking-induced genomic alterations, including methylation and somatic mutations. Validations of the corresponding features in mutant cell lines were achieved to some degrees. Several compounds which were sensitive to mutant subtype of lung adenocarcinoma were identified, such as inhibitors of PI3K/Akt and IGF1R signaling pathways. Conclusions: KEAP1/NFE2L2 mutant lung adenocarcinoma showed potential heterogeneities. The intrinsic heterogeneities of KEAP1/NFE2L2 were associated with immune microenvironment and smoking-related genomic aberrations.