Unravelling AURKB as a potential therapeutic target in pulmonary arterial hypertension using integrated transcriptomic analysis and pre-clinical studies

To illuminate new actionable targets involved in pulmonary vascular remodeling in pulmonary arterial hypertension (PAH), we performed RNA sequencing on pulmonary artery smooth muscle cells (PASMCs) isolated from PAH patients and control donors. We then enriched our own experiment with publicly available datasets. Aggregation of gene expression datasets followed by functional enrichment and connectivity map analyses on common upregulated genes in PAH-PASMCs revealed Aurora kinase B (AURKB), the enzymatic core of the chromosomal passenger complex with BIRC5, as a potential driver and therapeutic target in PAH. Using pharmacological and molecular tools, we demonstrated that inhibition of AURKB in PAH-PASMCs blocks cell cycle progression, induces cell death, and reverses the gene signature of PAH-PASMCs. In addition, we provided evidence that AURKBi-treated PAH-PASMCs that escape apoptosis, acquire a senescence-associated secretory phenotype. In vivo, AURKB inhibition using Barasertib significantly improved hemodynamics in two preclinical models of established PAH by attenuating pulmonary vascular remodeling. A therapeutic effect was also observed in precision-cut lung slices generated from human lungs, thus confirming the predictive value of AURKB interference as a potential therapeutic for PAH progression.Finally, we demonstrated that the combination of Barasertib with the anti-senescent agent UC2288 was more effective in reducing vascular remodeling than either drug alone.