BREAKING! SARS-CoV-2 Activates Epidermal Growth Factor Receptor Mediated Signaling, Inducing Survivin Expression Which Assists In Cancer Progression!

New alarming data has emerged from a study conducted by researchers from United Arab Emirates University, Khalifa Center for Biotechnology and Genetic Engineering-UAE and Qatar University that helps explain why many cancer patients upon contracting the SARS-CoV-2 tend to have high risk of disease severity and increased mortality. These study findings also help explain why many Post COVID individuals are developing accelerated and aggressive cancers.


 
Corresponding author Dr Rabah Iratni from the Department of Biology, College of Science, United Arab Emirates University told Thailand Medical News, “The study shockingly found that the SARS-CoV-2 Spike 1 protein tends to activates the Epidermal Growth Factor Receptor (EGFR) mediated signaling, inducing Survivin expression which assists in cancer progression!”
 
Survivin is an anti-apoptotic protein which belongs to the inhibitor of apoptosis (IAP) family and considered as the key marker for the activation of the survival pathway in cancer cells. Such a response was very consistent with the phosphorylation of AKT in cancer cells.
 
The ongoing COVID-19 pandemic is caused by the novel SARS-CoV-2 coronavirus. At the molecular and cellular levels, the SARS-Cov-2 uses its envelope glycoprotein, the spike S protein, to infect the target cells in the lungs via binding with their transmembrane receptor, the angiotensin-converting enzyme 2 (ACE2).
 
The study team wanted to investigate if other molecular targets and pathways may be used by SARS-Cov-2.
 
The team investigated the possibility for the spike 1 S protein and its receptor-binding domain (RBD) targeting the epidermal growth factor receptor (EGFR) and its downstream signaling pathway in vitro using the lung cancer cell line (A549 cells). Protein expression and phosphorylation was examined upon cell treatment with the recombinant full spike 1 S protein or RBD.
 
Shockingly, the study findings demonstrated for the first time the activation of EGFR by the Spike 1 protein associated with the phosphorylation of the canonical ERK1/2 and AKT kinases and an increase of Survivin expression controlling the survival pathway.
 
The study findings suggest the putative implication of EGFR and its related signaling pathways in SARS-CoV-2 infectivity and COVID-19 pathology.
 
The study findings may open new perspectives in the treatment of COVID-19 patients by targeting EGFR.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.05.10.491351v1
 
The study findings many provide a solid molecular and cellular rationale to explain the increased risk of infectivity by SARS-Cov-2 and its severity in cancer patients as recently reported by numerous past studies.
 
https://www.nature.com/articles/s43018-020-00120-5
 
https://pubmed.ncbi.nlm.nih.gov/32345594/
 
These studies showed that cancer patients were more vul nerable to the SAR-COV-2 infection. Although COVID-19 was reported to have low death rate ~2% in the general population, patients with cancer and COVID-19, have at least 3-fold increase in the death rate. These studies also showed that patients with lung cancer, gastrointestinal cancer or breast cancer had the highest frequency of critical symptoms including highest death rates. Patients with lung cancer and gastrointestinal cancer had a death rate of 18.18% and 7.69%, respectively. Interestingly, these studies also showed that cancer patients that received targeted therapy that includes the EGFR-tyrosine kinase inhibitors showed the lowest death rate compared to cancer patients who received immunotherapy, chemotherapy or surgery.
 
These studies also showed that study 27% of the cancer patients with COVID-19 developed clinical worsening and 17.4% died.
 
This new UAE study showed that SAR-COV-2 activates the EGFR and its downstream signaling pathways controlling cell survival and proliferation.
 
At the molecular level, the vitro data provide, for the first time, the evidence that SARS-Cov-2 Spike 1 protein activating EGFR and its downstream signaling pathways, AKT and ERK1/2. This is very consistent with the well-established concept of the hijacking of cell surface receptors and their activity/signaling by pathogens including viruses.
 
https://pubmed.ncbi.nlm.nih.gov/15573137/
 
https://www.sciencedirect.com/science/article/abs/pii/S0006295216300028
 
https://pubmed.ncbi.nlm.nih.gov/29866590/
 
https://www.frontiersin.org/articles/10.3389/fcell.2019.00200/full
 
Hence, this implies that pathogens like SARS-CoV-2 use GPCRs and RTKs at the cell surface of the target cells during the infection process leading to their entry in the target cells.
 
Interestingly, these previous studies also showed the role of EGFR and its downstream signaling pathways in viruses/bacteria pathogenicity being consistent with the findings on SARS-Cov-2 spike protein. Indeed, EGFR was shown to be important during influenza infection.
 
The current study findings showed that the Spike 1-induced AKT activation occurred in EGFR-dependent manner in A549 cells since it was blocked by EGFR blockade (AG1478). This supports the conclusion that the activation by Spike 1 of the AKT/survival axis depends on EGFR activation.
 
Also, the differential effects of Spike 1 and RBD suggests different mode of activation and/or molecular pathways involved. One possible explanation is that Spike 1 may directly target EGFR while RBD uses other targets at the cancer cell surface including ACE2 resulting in AKT and ERK1/2 phosphorylation independently on EGFR.
 
The study findings are consistent with direct targeting of EGFR/AKT pathway, but this does not rule out the alternative pathway consisting of the implication of the canonical ACE2 pathway via transactivation of EGFR at the cell surface or intracellular crosstalk between their intracellular pathways.
 
Further studies are required to demonstrate whether Spike 1 protein directly binds to EGFR or not and what would be the implication of the canonical ACE2 pathway. Even though, the study investigates all the aspects of EGFR-dependent pathways and SARS-Cov-2 infectivity, the study team believes that the data will pave the way towards further investigation the exact role of EGFR in SARS-CoV-2 infection and pathogenicity.

Thailand Medical News would like to add that considering that viral persistence in a major issue in many Post COVID individuals, of which those controlling the COVID-19 narratives are trying to conceal or downplay, we can expect an exponential rise in excess death rates in coming years from a variety of causes that are linked to SARS-CoV-2 such as heart failures, organ failures, strokes, CVST, sepsis, secondary opportunistic infections, neurodegenerative issues and more so from accelerated aggresive cancers!
 
For more on Cancer And SARS-CoV-2, keep on logging to Thailand Medical News.
 
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