Oncotarget

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MEK inhibitors reduce cellular expression of ACE2, pERK, pRb while stimulating NK-mediated cytotoxicity and attenuating inflammatory cytokines relevant to SARS-CoV-2 infection

Lanlan Zhou, Kelsey Huntington, Shengliang Zhang, Lindsey Carlsen, Eui-Young So, Cassandra Parker, Ilyas Sahin, Howard Safran, Suchitra Kamle, Chang-Min Lee, Chun Geun Lee, Jack A. Elias, Kerry S. Campbell, Mandar T. Naik, Walter J. Atwood, Emile Youssef, Jonathan A. Pachter, Arunasalam Navaraj, Attila A. Seyhan, Olin Liang and Wafik S. El-Deiry _

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Oncotarget. 2020; 11:4201-4223. https://doi.org/10.18632/oncotarget.27799

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Abstract

Lanlan Zhou1,2,3,4,5,10,*, Kelsey Huntington1,2,4,5,6,10,*, Shengliang Zhang1,2,3,4,5,10, Lindsey Carlsen1,2,4,5,6,10, Eui-Young So4,5,8, Cassandra Parker1,2,4,5,7,10, Ilyas Sahin1,2,4,5,8,10, Howard Safran4,5,8,10, Suchitra Kamle4,5,9,10, Chang-Min Lee4,5,9,10, Chun Geun Lee4,5,9,10, Jack A. Elias4,5,9,10, Kerry S. Campbell11, Mandar T. Naik10,12, Walter J. Atwood4,5,10,13, Emile Youssef14, Jonathan A. Pachter14, Arunasalam Navaraj1,2,3,4,5,10, Attila A. Seyhan1,2,3,4,5,10, Olin Liang4,5,8,10 and Wafik S. El-Deiry1,2,3,4,5,6,8,10

1 Brown Experimentalists Against COVID-19 (BEACON) Group, Brown University, Providence, RI 02912, USA

2 Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA

3 Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA

4 The Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI 02912, USA

5 Cancer Center at Brown University, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA

6 Pathobiology Graduate Program, Brown University, Providence, RI 02912, USA

7 Department of Surgery, Lifespan Health System and Warren Alpert Medical School, Brown University, Providence, RI 02912, USA

8 Hematology-Oncology Division, Department of Medicine, Lifespan Health System and Warren Alpert Medical School, Brown University, Providence, RI 02912, USA

9 Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA

10 Warren Alpert Medical School, Brown University, Providence, RI 02912, USA

11 Blood Cell and Development Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA

12 Department of Molecular Pharmacology, Physiology and Biotechnology, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA

13 Department of Molecular Biology, Cell Biology, and Biochemistry, Warren Alpert Medical School, Brown University, Providence, RI 02912, USA

14 Verastem Oncology, Needham, MA 02494, USA

* These authors contributed equally to this work

Correspondence to:

Wafik S. El-Deiry,email: wafik@brown.edu

Keywords: ACE2; TMPRSS2; SARS-CoV-2; COVID-19; pseudovirus

Received: October 05, 2020     Accepted: October 17, 2020     Published: November 17, 2020

Copyright: © 2020 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

COVID-19 affects vulnerable populations including elderly individuals and patients with cancer. Natural Killer (NK) cells and innate-immune TRAIL suppress transformed and virally-infected cells. ACE2, and TMPRSS2 protease promote SARS-CoV-2 infectivity, while inflammatory cytokines IL-6, or G-CSF worsen COVID-19 severity. We show MEK inhibitors (MEKi) VS-6766, trametinib and selumetinib reduce ACE2 expression in human cells. In some human cells, remdesivir increases ACE2-promoter luciferase-reporter expression, ACE2 mRNA and protein, and ACE2 expression is attenuated by MEKi. In serum-deprived and stimulated cells treated with remdesivir and MEKi we observed correlations between pRB, pERK, and ACE2 expression further supporting role of proliferative state and MAPK pathway in ACE2 regulation. We show elevated cytokines in COVID-19-(+) patient plasma (N = 9) versus control (N = 11). TMPRSS2, inflammatory cytokines G-CSF, M-CSF, IL-1α, IL-6 and MCP-1 are suppressed by MEKi alone or with remdesivir. We observed MEKi stimulation of NK-cell killing of target-cells, without suppressing TRAIL-mediated cytotoxicity. Pseudotyped SARS-CoV-2 virus with a lentiviral core and SARS-CoV-2 D614 or G614 SPIKE (S) protein on its envelope infected human bronchial epithelial cells, small airway epithelial cells, or lung cancer cells and MEKi suppressed infectivity of the pseudovirus. We show a drug class-effect with MEKi to stimulate NK cells, inhibit inflammatory cytokines and block host-factors for SARS-CoV-2 infection leading also to suppression of SARS-CoV-2-S pseudovirus infection of human cells. MEKi may attenuate SARS-CoV-2 infection to allow immune responses and antiviral agents to control disease progression.


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