Unraveling AURKB as a potential therapeutic target in pulmonary hypertension using integrated transcriptomic analysis and pre-clinical studies
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.
Authors
- Mónica S. Montesinos
- Huidong Chen (ORCID: https://orcid.org/0000-0001-6171-0880)
- Chanil Valasarajan (ORCID: https://orcid.org/0000-0002-0969-9044)
- Mégan Gilbert
- François Potus (ORCID: https://orcid.org/0000-0003-1745-6445)
- Yann Grobs (ORCID: https://orcid.org/0000-0003-3200-3241)
- Sandra Martineau
- Steeve Provencher (ORCID: https://orcid.org/0000-0001-7535-9972)
- Sébastien Bonnet (ORCID: https://orcid.org/0000-0001-5753-1900)
- Sarah‐Eve Lemay (ORCID: https://orcid.org/0000-0002-6625-9918)
- Charlotte Romanet (ORCID: https://orcid.org/0000-0003-3583-2758)
- Soni Savai Pullamsetti (ORCID: https://orcid.org/0000-0003-0440-8831)
- Olivier Boucherat
- Sandra Breuils‐Bonnet
- Mélanie Sauvaget
- Manon Mougin
- Reem El Kabbout
- Charlie Théberge
- Min Lü (ORCID: https://orcid.org/0000-0002-4191-4787)
- Keiko Yamamoto
- Christopher J. Bilodeau
- Andréanne Pelletier
- Alice Bourgeois
Institutions
- Max Planck Institute for Heart and Lung Research (DE)
- German Center for Lung Research (DE)
- Universities of Giessen and Marburg Lung Center (DE)
- Université Laval (CA)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.101964
- Citations
- 7
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé