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

Author(s): Lanlan Zhou ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ¹⁰ ^, ^* , Kelsey Huntington ¹ ^, ² ^, ⁴ ^, ⁵ ^, ⁶ ^, ¹⁰ ^, ^* , Shengliang Zhang ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ¹⁰ , Lindsey Carlsen ¹ ^, ² ^, ⁴ ^, ⁵ ^, ⁶ ^, ¹⁰ , Eui-Young So ⁴ ^, ⁵ ^, ⁸ , Cassandra Parker ¹ ^, ² ^, ⁴ ^, ⁵ ^, ⁷ ^, ¹⁰ , Ilyas Sahin ¹ ^, ² ^, ⁴ ^, ⁵ ^, ⁸ ^, ¹⁰ , Howard Safran ⁴ ^, ⁵ ^, ⁸ ^, ¹⁰ , Suchitra Kamle ⁴ ^, ⁵ ^, ⁹ ^, ¹⁰ , Chang-Min Lee ⁴ ^, ⁵ ^, ⁹ ^, ¹⁰ , Chun Geun Lee ⁴ ^, ⁵ ^, ⁹ ^, ¹⁰ , Jack A. Elias ⁴ ^, ⁵ ^, ⁹ ^, ¹⁰ , Kerry S. Campbell ¹¹ , Mandar T. Naik ¹⁰ ^, ¹² , Walter J. Atwood ⁴ ^, ⁵ ^, ¹⁰ ^, ¹³ , Emile Youssef ¹⁴ , Jonathan A. Pachter ¹⁴ , Arunasalam Navaraj ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ¹⁰ , Attila A. Seyhan ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ¹⁰ , Olin Liang ⁴ ^, ⁵ ^, ⁸ ^, ¹⁰ , Wafik S. El-Deiry ¹ ^, ² ^, ³ ^, ⁴ ^, ⁵ ^, ⁶ ^, ⁸ ^, ¹⁰

Publication date (Electronic): 17 November 2020

Journal: Oncotarget

Publisher: Impact Journals LLC

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

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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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Clinical Characteristics of Coronavirus Disease 2019 in China

Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)

Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)

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SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)

Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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Remdesivir for the Treatment of Covid-19 — Final Report

John H. Beigel, Kay Tomashek, Lori Dodd … (2022)

Abstract Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)

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Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Impact Journals LLC

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 17 November 2020

Publication date (Electronic): 17 November 2020

Volume: 11

Issue: 46

Pages: 4201-4223

Affiliations

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

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

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

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

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

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

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

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

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

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

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

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

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

¹⁴Verastem Oncology, Needham, MA 02494, USA

^*These authors contributed equally to this work

Author notes

Correspondence to: Wafik S. El-Deiry, email : wafik@ 123456brown.edu

Article

Publisher ID: 27799

DOI: 10.18632/oncotarget.27799

PMC ID: 7679035

PubMed ID: 33245731

SO-VID: 1bb77fcb-48aa-4458-a39d-7f9eef2c87cf

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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.

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

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Abstract

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Novel Coronavirus Disease COVID-19

Most cited references 55

Clinical Characteristics of Coronavirus Disease 2019 in China

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Remdesivir for the Treatment of Covid-19 — Final Report

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