2. Academic Validation
  3. Unraveling AURKB as a potential therapeutic target in pulmonary hypertension using integrated transcriptomic analysis and pre-clinical studies

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

  • Cell Rep Med. 2025 Feb 18;6(2):101964. doi: 10.1016/j.xcrm.2025.101964.
Sarah-Eve Lemay 1,  Manon Mougin 1,  Mélanie Sauvaget 1,  Reem El Kabbout 1,  Chanil Valasarajan 2,  Keiko Yamamoto 1,  Sandra Martineau 1,  Andréanne Pelletier 1,  Coralie Bilodeau 1,  Yann Grobs 1,  Alice Bourgeois 1,  Charlotte Romanet 1,  Sandra Breuils-Bonnet 1,  Monica S Montesinos 3,  Min Lu 3,  Huidong Chen 3,  Mégan Gilbert 1,  Charlie Théberge 1,  François Potus 4,  Soni Pullamsetti 5,  Steeve Provencher 4,  Sébastien Bonnet 6,  Olivier Boucherat 7
Affiliations

Affiliations

  • 1 Pulmonary Hypertension Research Group, Québec Heart and Lung Institute Research Centre, Québec City, QC, Canada.
  • 2 Max Planck Institute for Heart and Lung Research, Department of Lung Development and Remodeling, German Center for Lung Research (DZL), Bad Nauheim, Germany.
  • 3 Morphic Therapeutic, Inc, Waltham, MA, USA.
  • 4 Pulmonary Hypertension Research Group, Québec Heart and Lung Institute Research Centre, Québec City, QC, Canada; Department of Medicine, Laval University, Québec City, QC, Canada.
  • 5 Max Planck Institute for Heart and Lung Research, Department of Lung Development and Remodeling, German Center for Lung Research (DZL), Bad Nauheim, Germany; Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), DZL, Justus Liebig University, member of the German Center for Lung Research (DZL), Giessen, Germany.
  • 6 Pulmonary Hypertension Research Group, Québec Heart and Lung Institute Research Centre, Québec City, QC, Canada; Department of Medicine, Laval University, Québec City, QC, Canada. Electronic address: sebastien.bonnet@criucpq.ulaval.ca.
  • 7 Pulmonary Hypertension Research Group, Québec Heart and Lung Institute Research Centre, Québec City, QC, Canada; Department of Medicine, Laval University, Québec City, QC, Canada. Electronic address: olivier.boucherat@criucpq.ulaval.ca.
PMID: 39933527 DOI: 10.1016/j.xcrm.2025.101964
Abstract

Despite advances in treatment, the prognosis for patients with pulmonary arterial hypertension (PAH) remains dismal, highlighting the need for further therapeutic advances. By using RNA Sequencing on pulmonary artery smooth muscle cells (PASMCs), functional enrichment, and connectivity map analyses, we identify Aurora Kinase B (AURKB) as a candidate therapeutic target. We show that AURKB inhibition blocks cell cycle progression and reverses the gene signature of PAH-PASMCs. We also report that PAH-PASMCs that escape Apoptosis acquire a senescence-associated secretory phenotype. In vivo, AURKB inhibition using barasertib improves hemodynamics in two preclinical models of established PAH by attenuating pulmonary vascular remodeling. A therapeutic effect is also observed in human precision-cut lung slices. Finally, we demonstrate that the combination of barasertib with a p21 attenuator is more effective in reducing vascular remodeling than either drug alone. These findings provide insight into strategies for therapeutic manipulation.

Keywords

FOXM1; aurora kinase B; mitosis; pulmonary arterial hypertension; right ventricular failure; senescence; vascular remodeling.

Figures
Products