Approved Lung Cancer Therapy Dacomitinib Shows Promise in Treating PAH, Animal Study Finds
Dacomitinib, a medicine recently approved by the U.S. Food and Drug Administration for the treatment of certain forms of lung cancer, showed promising therapeutic effects in two animal models of pulmonary arterial hypertension (PAH), a study reports.
In PAH, the structure of blood vessels in the lungs is altered as a result of increased proliferation, resistance to apoptosis (a form of programmed cell death), and migration of pulmonary vascular cells. These alterations, known as vascular remodeling, increase the thickness of the vessels and the resistance to blood flow.
These vessel changes are regulated by molecules produced in the body, known as growth factors, including the epidermal growth factor (EGF), which acts by binding to cell surface receptors known as the epidermal growth factor receptor (EGFR) family.
Dacomitinib works by inhibiting three of the four members of the EGFR family.
Previous studies suggested that EGFR plays a role in PAH progression. However, EGFR inhibitors tested in animal models of PAH only inhibited one or two EGFRs, and showed limited therapeutic effects.
In the current study, researchers at Harbin Medical University in Daqing, China, tested the effects of dacomitinib in two independent rat models of PAH.
Results showed that right ventricular systolic pressure — a measure of how much resistance the heart has to overcome to pump blood into the lungs — was significantly reduced in these animals after treatment with dacomitinib.
Dissection of the hearts also showed less hypertrophy of the right ventricle, and echocardiographic measurements showed favorable effects of dacomitinib in the animal models of PAH.
Dacomitinib also reduced the thickness of lung vessels, the amount of deposited collagen, and the levels of EGFR in pulmonary arteries.
To better understand the effects of dacomitinib at the cellular level, the investigators used primary rat pulmonary smooth muscle cells (PASMCs). Smooth muscle cells surround blood vessel walls and regulate their diameter.
Results showed that dacomitinib inhibited the proliferation, migration, and cell cycle progression of PASMCs subjected to hypoxia (low oxygen levels), and modulated other cellular processes involved in PAH. Hypoxia is one the conditions that triggers pulmonary vascular remodeling.
A cellular signaling pathway known as PI3K-AKT-mTOR was found to play a key role in mediating the effects of dacomitinib. This pathway regulates the cell cycle, the “clock” that controls when cells proliferate.
The team concluded that “dacomitinib inhibited hypoxia-induced cell cycle progression, proliferation, migration, and autophagy of PASMCs, thereby attenuating pulmonary vascular remodeling and development of PAH via the PI3K-AKT-mTOR signaling pathway.”
The team believes that given the therapeutic efficacy exhibited by dacomitinib in the experimental animal models of PAH, “dacomitinib may serve as new potential therapeutic for the treatment of PAH.”