Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis

Fibroblast activation including proliferation, survival, andECMproduction is central to initiation and maintenance of fibrotic lesions in idiopathic pulmonary fibrosis (IPF). However, druggable molecules that target fibroblast activation remain limited. In this study, we show that multiple pro-fibrotic growth factors, includingTGF alpha,CTGF, andIGF1, increase aurora kinase B (AURKB) expression and activity in fibroblasts. Mechanistically, we demonstrate that Wilms tumor 1 (WT1) is a key transcription factor that mediatesTGF alpha-drivenAURKBupregulation in fibroblasts. Importantly, we found that inhibition ofAURKBexpression or activity is sufficient to attenuate fibroblast activation. We show that fibrosis induced byTGF alpha is highly dependent onAURKBexpression and treatingTGF alpha mice with barasertib, anAURKBinhibitor, reverses fibroblast activation, and pulmonary fibrosis. Barasertib similarly attenuated fibrosis in the bleomycin model of pulmonary fibrosis. Together, our preclinical studies provide important proof-of-concept that demonstrate barasertib as a possible intervention therapy forIPF.