Aurora kinase B: A New Therapeutic Target in PAH

Pulmonary arterial hypertension (PAH) is characterized by pulmonary artery (PA) remodeling leading to right ventricular failure and premature death. Extensive proliferation of PA smooth muscle cells (PASMCs) is perhaps the most important feature of PAH accounting for vascular remodeling. To discover novel actionable targets involved in vascular remodeling, we performed a comparative RNA-sequencing analysis between control and PAH-PASMCs. Data aggregation with publicly available datasets followed by drug connectivity mapping and functional analysis (RNA-Seq) identified aurora kinase B (AURKB) inhibitors as reversers of the PAH-PASMC signature. Further experiments revealed that FOXM1 positively regulates AURKB. Pharmacological (Barasertib) and molecular inhibition of AURKB reduced PAH-PASMC proliferation (EDU incorporation, Ki67 & PLK1 expression), survival (Tunel, Annexin V & Survivin expression) and was associated with accumulation of mitotic defects. Acquisition of a senescence-like phenotype was observed in PAH-PASMCs that escaped apoptosis following AURKB inhibition (SA- βGal, RNA-Seq, p21, p53, SASP…). Barasertib treatment significantly improved pulmonary vascular remodeling and hemodynamics in MCT and Su/Hx rats with established PAH (RHC & EVG). A therapeutic effect was also observed in human precision-cut lung slices. Finally, the combination of Barasertib with the p21 attenuator UC2288 was more effective in reducing vascular remodeling in Su/Hx rats than either drug alone (EVG). Our research identified AURKB as a novel therapeutic target and suggests that combining anti-remodeling drugs with senotherapeutics may be more effective in counteracting vascular remodeling in PAH.