Connectivity Map and perturbation-based sensitivity analysis identifies MEK inhibitors as senolytics in human lung fibroblasts

Abstract

Recently, the elimination of the disease-associated accumulation of senescent cells using senolytics has been shown to exert health benefits in animal studies. However, due to the heterogeneity of cell senescence and its unrecognized master regulators, drug development faces a complexity that must be handled. Bioinformatic elucidation of genes and pathways involved in senolysis and prediction of senolytic activity of compounds can cut costs and facilitate faster achievements in the field. In the present investigation, after obtaining the consensus gene signature of senescent fibroblasts of lung origin and deriving its anti-apoptotic module, we utilized Connectivity Map (CMap) alongside small molecule and genetic perturbation sensitivity data in cancer cell lines to identify drugs and genetic interventions that might induce apoptosis or sensitize senescent cells to apoptosis. Through bioinformatic evaluations, we speculate that activation of early stages of autophagy which contributes to the formation of autophagosomes, concurrent with the activation of waste protein concealment system by the mean of p62 and chaperoning system alongside an increase in JUNB gene expression can secure the survival of the senescent cells even when homeostasis of different cellular processes is disrupted. Moreover, our bioinformatic evaluation proposed selumetinib, a MEK inhibitor, as a senolytic against senescent lung fibroblasts. The senolytic activity of a variety of MEK inhibitors in senescent lung fibroblasts was confirmed using human lung fibroblasts in vitro.