Identification and Characterization of Senescence Phenotype in Lung Adenocarcinoma with High Drug Sensitivity

Lung adenocarcinoma (LUAD) is a major health problem and has poor prognosis. Heterogeneity is a central determinant of the treatment outcome, requiring identification of new subclasses of LUAD. Senescence has emerged as a crucial regulator of metastasis and drug response. Ionizing radiation- and doxorubicin-induced senescence-associated genes in lung fibroblasts were used in K-means clustering to identify high- and low-senescence (HS and LS) classes among The Cancer Genome Atlas- LUAD (TCGA-LUAD) patients. The LS group showed significantly poorer survival (P = 0.01) and greater activation of proliferative signaling pathways, proliferation, wound healing, and genetic aberrations (P < 0.05). The TP53 mutation rate was significantly greater in the HS group (P < 0.0001), explaining the phenotype. Also, genome-wide hypomethylation was significantly greater in the LS group than in the HS group. Interestingly, pathway analysis identified silencing of Wnt signaling in the HS group. The machine learning-based recursive feature elimination technique was used to identify a 20-gene senescence signature in TCGA-LUAD samples. The presence of a senescence phenotype with poor survival was validated in an independent patient cohort and a cell-line cohort using unsupervised clustering of samples based on a 20-gene signature. On further analysis, HS cells were more resistant to drugs, particularly histone deacetylase inhibitors. Taken together, this study identified a novel subtype of LUAD with reduced Wnt signaling and high drug resistance.