Abstract
A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19.
Highlights
The COVID-19 pandemic, which is caused by the novel coronavirus severe acute respiratory syndrome (SARS)-CoV-2, has impacted healthy individuals, but more importantly, people with comorbidity medical conditions such as diabetes, lung diseases, and cancer [1]
A reporter system of the angiotensin-converting enzyme 2 (ACE2) promoter was used to assess the effects of a panel of Tyrosine kinase inhibitors (TKIs) on the promoter activity in which the luciferase reporter gene was driven by the proximal ACE2 promoter (−1119 to +103 nt [7]) (Figure 1A)
The reporter plasmid was transiently transfected into the human embryonic kidney cells HEK293, which were treated with different TKIs, including the epithelial growth factor receptor (EGFR) inhibitors gefitinib, erlotinib, lapatinib, and afatinib, as well as imatinib
Summary
The COVID-19 pandemic, which is caused by the novel coronavirus SARS-CoV-2, has impacted healthy individuals, but more importantly, people with comorbidity medical conditions such as diabetes, lung diseases, and cancer [1]. SARS-CoV-2 infection poses a significant threat to cancer patients, and the associated morality seems to be determined by age, gender, and comorbidities, but the potential relationships of patients’. Anti-cancer treatments with the susceptibility of virus infection remain elusive [2]. (ACE2), the major receptor on the cell surface for the protease-processed spike protein of the virus during cell entry [3,4]. Tyrosine kinase inhibitors (TKIs) are the major medicines of targeted therapy for cancer treatment; their impacts on COVID-19 infection are not well understood. As an initial effort to understand the potential influence of cancer treatments on SARS-CoV-2 infection, the current study tested a panel of FDA-approved. We chose to begin by assessing the regulation of ACE2 expression in vitro and in vivo and examining the cell entry activity of the SARSCoV-2 pseudoviral particles
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