Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis.

Rajesh K Kasam, Sudhir Ghandikota, Divyalakshmi Soundararajan, Geereddy B Reddy, Steven K Huang, Anil G Jegga, Satish K Madala

EMBO molecular medicine 2020 Sep 07

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Fibroblast activation including proliferation, survival, and ECM production 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, including TGFα, CTGF, and IGF1, increase aurora kinase B (AURKB) expression and activity in fibroblasts. Mechanistically, we demonstrate that Wilms tumor 1 (WT1) is a key transcription factor that mediates TGFα-driven AURKB upregulation in fibroblasts. Importantly, we found that inhibition of AURKB expression or activity is sufficient to attenuate fibroblast activation. We show that fibrosis induced by TGFα is highly dependent on AURKB expression and treating TGFα mice with barasertib, an AURKB inhibitor, 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 for IPF. © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Citation

Rajesh K Kasam, Sudhir Ghandikota, Divyalakshmi Soundararajan, Geereddy B Reddy, Steven K Huang, Anil G Jegga, Satish K Madala. Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis. EMBO molecular medicine. 2020 Sep 07;12(9):e12131