COVID-19 News: SARS-CoV-2 Triggers Epidermal Growth Factor Receptor Signaling Pathway, Leading To Lung Fibrosis And Lung Cancer! Erlotinib Helps!

COVID-19 News: The relentless evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not only given rise to varying viral strains but also ushered in the imperative need for effective therapeutics. The battle against COVID-19 extends beyond immediate symptoms to the long-term health implications, as seen in cases of long COVID-19. In this quest for solutions, a closer examination of the epidermal growth factor receptor (EGFR) signaling pathway and the potential of targeting it emerges as a promising avenue. This COVID-19 News report delves into the intricacies of EGFR signaling during SARS-CoV-2 infection and explores the efficacy of the EGFR inhibitor, erlotinib, as a therapeutic strategy.


Erlotinib
 
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The Landscape of SARS-CoV-2 Infection
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has unleashed a plethora of challenges, from acute symptoms to complications such as organ dysfunction, pulmonary fibrosis, and the enigmatic long COVID-19. Despite the development and deployment of vaccines, the emergence of new viral variants continually threatens the efficacy of existing preventive measures. This necessitates a constant exploration of innovative therapeutic options to alleviate the health and societal impacts of COVID-19.
 
Unveiling the EGFR Signaling Pathway
EGFR: A Molecular Maestro
At the heart of cellular processes lies the epidermal growth factor receptor (EGFR), a 170-kDa transmembrane glycoprotein belonging to the receptor tyrosine kinase (RTK) family. Comprising a transmembrane domain, extracellular ligand-binding domain, regulatory domain, and a cytoplasmic tyrosine kinase-containing domain, EGFR plays a pivotal role in transducing signals that regulate cell survival, proliferation, and differentiation.
 
Activation Cascades
EGFR activation occurs in response to ligands like epidermal growth factor (EGF) or transforming growth factor alpha (TGF-α). This activation leads to homo or heterodimer formation between receptors, a critical step for the subsequent activation of intracellular tyrosine kinase domains and C-terminal tail phosphorylation. The phosphorylation of tyrosine residues initiates downstream signaling cascades, including extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3 kinase (PI3K)/AKT, Janus kinase (JAK), p38 mitogen-activated protein kinases (MAPKs), and signal transducers and activation of transcription (STAT) pathways.
 
EGFR Signaling and SARS-CoV-2 Infection
Activation during Infection
SARS-CoV-2, the culprit behind COVID-19, intricately manipulates cellular processes, particularly the EGFR signaling pathway. The virus achieves this by binding to the S1 subunit and receptor-binding domain (RBD) of the S protein, setting off a cascade of events. This interaction not only facilitates viral entry but also promotes phosphorylation of EGFR, Akt, and ERK1/2. The activation of EGFR is further confirmed by its interaction with the S protein in various cellular contexts.
 
Significance in Disease Pathogenesis
The activation of EGFR during SARS-CoV-2 infection triggers downstream signaling pathways that contribute to various facets of COVID-19 pathogenesis. These include facilitating virus internalization, hyperproduction and secretion of mucus, stimulation of inflammation, compromise of the host's antiviral activity, and the induction of pulmonary fibrosis. Notably, EGFR mutations, common in non-small cell lung cancer (NSCLC), underscore the potential link between COVID-19 and lung cancer development.
 
Implications for Pulmonary Fibrosis and Mucus Hypersecretion
Role in Fibrosis
EGFR activation, often associated with cancer, also plays a critical role in the development of pulmonary fibrosis. Dysregulated activation of EGFR, leading to hyperproliferation and metaplasia in alveolar epithelial cells, contributes to progressive lung fibrosis and carcinogenesis. The long-term consequences of COVID-19-induced pulmonary fibrosis are becoming increasingly evident, with survivors exhibiting signs of fibrosis months after the acute infection.
 
Mucus Hypersecretion
Another clinical hallmark of COVID-19 is mucus hypersecretion, which is orchestrated, in part, by EGFR activation. The binding of EGF or EGF-like ligands stimulates the expression of mucin genes, particularly MUC5AC and MUC2, through the ERK and Erk1/2 signaling pathways. Excessive mucus production not only contributes to pulmonary inflammation and hypoxia but also correlates with increased morbidity and mortality in COVID-19 patients.
 
Significance of Targeting EGFR Signaling
The intricate involvement of EGFR in both viral infections and tumorigenesis establishes it as a potential therapeutic target for COVID-19. Recognizing the dual role of EGFR inhibitors (EGFRIs) as both anticancer agents and antiviral compounds opens up avenues for repurposing existing drugs to combat SARS-CoV-2.
 
FDA-Approved EGFR Inhibitors
A comprehensive analysis of FDA-approved EGFRIs reveals two main categories: tyrosine kinase inhibitors (TKIs) and monoclonal antibodies. These inhibitors, designed to modulate EGFR signaling, exhibit not only anticancer efficacy but also antiviral activity. Examples such as pictilisib, omipalisib, and sorafenib, known for their downstream signaling inhibition, showcase significant reductions in SARS-CoV-2 replication.
 
Erlotinib: The Chosen One
Among the array of FDA-approved EGFRIs, erlotinib emerges as a superior candidate for COVID-19 treatment. Erlotinib, a low molecular-weight TKI, has proven efficacy in treating advanced pancreatic cancer and NSCLC. Its ability to inhibit EGFR phosphorylation, block viral entry, reduce mucus hyperproduction, and mitigate the expression of TNF-α positions it as a multifaceted weapon against SARS-CoV-2.
 
Erlotinib as a Promising Antiviral Drug
Multifaceted Mechanisms of Action
Erlotinib's potential as a COVID-19 drug lies in its ability to disrupt various stages of the viral life cycle. By inhibiting EGFR and AAK1 (AP2-associated kinase 1), erlotinib not only impedes virus entry but also suppresses intracellular assembly and spread of viral particles. Additionally, erlotinib's inhibition of TNF-α expression and its impact on T cell activation contribute to its effectiveness in alleviating inflammation, a hallmark of severe COVID-19.

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Previous Efficacy and Known Toxicity
Erlotinib's efficacy is not merely theoretical; it has demonstrated antiviral potency in both in vitro and in vivo studies. Furthermore, previous studies have explored its use in managing COVID-19, showcasing its potential as a therapeutic intervention. However, concerns about erlotinib's toxicity, such as interstitial pneumonia observed in cancer treatments, need to be considered. The shorter duration of erlotinib use in antiviral applications may alleviate some of these concerns.
 
Future Perspectives and Conclusions
As the world grapples with the multifaceted challenges posed by the COVID-19 pandemic, the exploration of novel therapeutic avenues, such as repurposing drugs like erlotinib, gains significance. The proposed strategy, grounded in the scientific understanding of EGFR signaling in the context of SARS-CoV-2 infection, opens new doors for potential interventions. However, the translation of these findings into clinical practice necessitates rigorous evaluation through well-designed and diverse clinical trials.
 
Future Research Directions
Future research should aim to elucidate the impact of erlotinib on various aspects, including EGFR activation, downstream signaling pathways, disease severity, mortality rates, and safety profiles across diverse populations. Additionally, investigating the potential synergy of erlotinib with other antiviral agents could enhance its therapeutic efficacy.
 
Conclusion
In conclusion, the intricate interplay between the EGFR signaling pathway and SARS-CoV-2 infection unveils a complex landscape that extends beyond immediate symptoms. Erlotinib, with its proven efficacy in cancer treatment and multifaceted actions against SARS-CoV-2, emerges as a compelling candidate in the arsenal against COVID-19. As the global health community strives to overcome the challenges posed by the virus, a scientific and innovative approach to therapeutic strategies remains imperative. The journey to decode the mysteries of COVID-19 and identify effective interventions continues, with EGFR signaling and erlotinib standing out as promising avenues in this ongoing battle.
 
The study findings were published in the peer reviewed journal: Reviews in Medical Virology.
https://onlinelibrary.wiley.com/doi/10.1002/rmv.2500
 
Thailand Medical News will be doing a follow-up article on this study as to how certain phytochemicals and also certain supplements are able to do work eve better than erlotinib with no long-term side effects.

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