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 First Author: Fei Li 

Journal/preprint name: bioRxiv 

Paper DOIhttps://doi.org/10.1101/2020.09.11.293035 

Tags: TMPRSS2, mechanism, enzalutamide, lung cancer, organoids 

Summary 

The authors aimed to characterize the antiviral efficacy of enzalutamide, an antiandrogen agent, on transmembrane serine protease 2 (TMPRSS2) expression. TMPRSS2 is a key component in mediating SARS-CoV-2 entry into host cells and has been shown to be reduced in prostate cancer cells following enzalutamide treatment. Enzalutamide efficiently blocked entry of SARS-CoV-2 in prostate cancer cells, however there was no antiviral activity in mouse and human lung epithelial cells due to independence of TMPRSS2 expression of androgen receptor (AR) in the lung. Therefore, they conclude that enzalutamide is unlikely to exhibit any antiviral effect in COVID-19 treatment. 

Research Highlights

  1.  AR inhibition can prevent SARS-CoV-2 infection through reduction of TMPRSS2 expression in the prostate 

  1. Using lung cancer cells as well as organoids showed that TMPRSS2 expression was independent of AR expression in the lung 

  1. Application of Ad-ACE2 transduced mouse models confirmed in vitro results that enzalutamide did not inhibit SARS-CoV-2 entry into host lung cells 

  1. Distinct AR binding pattern between prostate and lung cells identified using ATAC-seq and ChIP-seq 

Impact for COVID-19 research:  

The drug enzalutamide was proposed as a promising drug reducing the expression of TMPRSS2, however in this study, the authors found an organ-specific regulation of TMPRSS2. The authors demonstrated that expression of TMPRSS2 in the lung is independent of AR, and therefore enzalutamide treatment does not modulate TMPRSS2 expression in lung cells 

Methodologies: 

  • Study Typein vitro, in vivo mouse models 

  • Important cell lines/viral models used: Pseudovirus, full SARS-CoV-2 virus (isolated from clinical case), LNCaP & VCaP (prostate cancer cell lines), A549, H1437 & H2126 (lung cancer cell lines), lung organoids, Ad-ACE2-transduced mouse model 

  • Key Techniques: ATAC-seqCHiP-seq, immunofluorescence, luciferase assay, qRT-PCR 

Limitations: 

  • Although AR and TMPRSS2 stainings were implemented in the lung, no colocalization has been applied 

  • No consideration of human lung microenvironment with stromal cells potentially displaying antiviral activity following enzalutamide treatment