Integrated transcriptomics reveals master regulators of lung adenocarcinoma and novel repositioning of drug candidates.

backgroundLung adenocarcinoma is the major cause of cancer-related deaths in the world. Given this, the importance of research on its pathophysiology and therapy remains a key health issue. To assist in this endeavor, recent oncology studies are adopting Systems Biology approaches and bioinformatics to analyze and understand omics data, bringing new insights about this disease and its treatment.

methodsWe used reverse engineering of transcriptomic data to reconstruct nontumorous lung reference networks, focusing on transcription factors (TFs) and their inferred target genes, referred as regulatory units or regulons. Afterwards, we used 13 case-control studies to identify TFs acting as master regulators of the disease and their regulatory units. Furthermore, the inferred activation patterns of regulons were used to evaluate patient survival and search drug candidates for repositioning.

resultsThe regulatory units under the influence of ATOH8, DACH1, EPAS1, ETV5, FOXA2, FOXM1, HOXA4, SMAD6, and UHRF1 transcription factors were consistently associated with the pathological phenotype, suggesting that they may be master regulators of lung adenocarcinoma. We also observed that the inferred activity of FOXA2, FOXM1, and UHRF1 was significantly associated with risk of death in patients. Finally, we obtained deptropine, promazine, valproic acid, azacyclonol, methotrexate, and ChemBridge ID compound 5109870 as potential candidates to revert the molecular profile leading to decreased survival.

conclusionUsing an integrated transcriptomics approach, we identified master regulator candidates involved with the development and prognostic of lung adenocarcinoma, as well as potential drugs for repurposing.