Multi-omics Analysis reveals novel therapeutic vulnerabilities in lung cancer

Non-small cell lung cancer (NSCLC) comprises the majority (~85%) of all lung tumors, with lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) being the most frequently diagnosed histological subtypes. Currently, multi-modal omics profiles had been carried out in NSCLC, but no studies reported yet a systems biology approach to provide a complete picture of molecular perturbations specifically for LUAD and LUSC. Overall design: In this study, we integrated transcriptomics, metabolomics and adducteomics for the first time to analyze 30 paired human lung tumors and adjacent noncancerous tissues. We portrayed unique metabolite related gene signatures to distinguish LUAD from LUSC and several altered pathways aberrantly expressed at both transcriptional and metabolic levels. Additionally, the integration studies revealed a 28-metabolite gene signature in TCGA-LUAD cohort and demonstrated a significant association with survival, especially for 6 metabolite related genes as therapeutic targets. To further explore, we identified AZD-6482, a clinical trial drug from LINCS/connectivity map and found that it significantly inhibited 3 genes from the 28-gene signature. By integrating adducteomics, we found a differential expression of 307 genes correlated with 6 DNA adducts in LUSC although LUAD did not show much correlation. We found that ?-hydroxy-propanodeoxyguanosine (?-OH-PdG) is the major DNA adduct formed in LUSC, but not in adjacent noncancerous tissue and significantly correlated with 295 modulated genes as well. We also have identified aberrant signaling pathways for each specific DNA adducts in LUSC compared to adjacent normal. Overall, we have provided a broad picture of integration of omics that can distinguish LUAD and LUSC, prediction of patient survival and identification of therapeutic targets and anticancer drugs. Ultimately, genes modulated by DNA adducts in LUSC could serve as biomarkers or therapeutic targets for cigarette smoke induced lung cancer.