The blockade of Aurora kinase B activity using Barasertib attenuates lung fibrosis

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Inhibition of Aurora Kinase B attenuates fibroblast activation and pulmonary fibrosis

Why is this study important?

The lungs are indispensable life-sustaining organs whose function is to absorb oxygen and expel gases, such as carbon dioxide. It is crucial for gaseous exchange and functioning of multiple organs in the body. The loss in the structural architecture and function of the lungs during infections and injury can result in death. The lungs are made up of several different types of cells, offers structural and functional support to the cells. Majorly, ECM contains proteins like collagen, elastin, fibronectin, and laminins. A well-balanced composition and organization of ECM are very important for the lungs to function properly.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that develops over a period of time because of excessive accumulation of ECM components leading to thickening and scarring of the lungs, and the cause for IPF is unknown (idiopathic). IPF is one of the most fatal fibrotic lung diseases in the United States and Asian countries, including India. Majorly, it affects the elderly population [1]. It causes death within 3-5 years from the time of. Currently, a couple of drugs are used to slow down the disease progression but none of them can prevent the mortality in patients with IPF [2]. Hence, further research is required to identify molecular targets that can help develop drugs to combat this disease effectively.

Fibroblasts, one of the important cell types in the lung, have the capability to become myofibroblasts and both these cell types secrete extracellular matrix components. During normal wound healing, fibroblasts and myofibroblasts are cleared by a programmed cell death process called apoptosis that removes unwanted cells in the body; but in IPF, as a result of persistent (unknown) insult, fibroblasts undergo uncontrolled proliferation and become myofibroblasts with a capacity to secrete large quantities of ECM. Importantly, myofibroblasts become resistant to death by apoptosis, and their contractile forces contribute to structural deformation in the lung, ultimately affecting lung function [3]. Therefore, identifying the molecules that regulate the proliferation of fibroblasts and clearance of myofibroblasts is key to develop new therapies for IPF.


How did we do and what did we find in this study?

Aurora Kinase B (AURKB) helps during the cell division and was found to be overexpressed in multiple cancers [4]. Our focus was to understand the AURKB’s role in lung fibrosis; and initially, we observed increased AURKB expression selectively in lung fibroblasts of IPF patients and also in mouse models of fibrotic lung disease. We demonstrated that increase in AURKB expression is mediated by Wilms’ Tumor 1 (WT1), a previously identified pro-fibrotic transcription factor [5]. Later, we isolated fibroblasts and myofibroblasts from IPF patient’s lung to further understand the AURKB’s role in fibroblast proliferation and clearance. Notably, inhibition of AURKB expression by siRNA in lung fibroblasts from IPF patients has resulted in decreased fibroblast proliferation and increased myofibroblast clearance by apoptotic death. Expression of genes that control fibroblast proliferation and myofibroblasts resistance to death was altered in AURKB knockdown fibroblasts.

Barasertib (also known as AZD1152) is a small molecule inhibitor that specifically binds and inhibits AURKB protein activity. Currently, Barasertib is in the various phases of clinical trials for leukemia [6]. Interestingly, we noticed that Barasertib treatment resulted in decreased fibroblasts proliferation and increased myofibroblasts clearance in vitro. Expression of genes that regulate cell proliferation and apoptosis is also impacted in Barasertib treated fibroblasts isolated from IPF patient’s lung. These studies suggest, targeting AURKB either genetically or pharmacologically decreased fibroblast proliferation or increased myofibroblasts clearance by regulating genes involved in the respective processes.

Mice that overexpress transforming growth factor-α (TGFα) specifically in the lung epithelial cells get fibrosis and can be used as a model of fibrotic lung disease. Administering Barasertib intraperitoneally along with TGFα overexpression for 28 days, protected mice from developing fibrotic lung disease. Also, to test Barasertib efficacy in reversing established fibrosis, mice that had fibrotic lung disease are treated with Barasertib for 21 days. Studies revealed decreased ECM components (such as collagens) and improved lung architecture and function in mice treated with Barasertib. Importantly, Barasertib treated fibrotic mice showed decreased mesenchymal proliferation in fibrotic lesions. Similarly, therapeutic treatment with Barasertib attenuated Bleomycin-induced lung fibrosis in mice.

Collectively, these studies aided in identifying AURKB as a promising molecule that can be targeted using a small-molecule inhibitor Barasertib for pulmonary fibrosis. Future mechanistic studies aiming to understand the AURKB-WT1 axis and Barasertib as an effective molecule to target IPF either alone or as a combination therapy are needed. Developing effective therapies for IPF is imperative considering its prevalence and survival rate in most developing countries, and our study paves the way to address this.


  1. Cellular and molecular mechanisms of fibrosis.
  2. New therapeutics based on emerging concepts in pulmonary fibrosis.
  3. Fibroblasts in fibrosis: novel roles and mediators.
  4. Aurora kinases: novel therapy targets in cancers.
  5. Wilms’ tumor 1 drives fibroproliferation and myofibroblast transformation in severe fibrotic lung disease.
  6. Barasertib (AZD1152), a Small Molecule Aurora B Inhibitor, Inhibits the Growth of SCLC Cell Lines In Vitro and In Vivo.


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