Expression of SARS-CoV-2 Related Surface Proteins in Non-Small Cell Lung Cancer Patients and the Influence of Standard of Care Therapy
29 Pages Posted: 25 Feb 2022
Abstract
Objectives: We aimed to study the expression of SARS-CoV-2-related surface proteins on non-small cell lung cancer (NSCLC) cells and identify clinicopathological characteristics that are related to increased ACE2 protein expression and soluble (s)ACE2 levels with a particular focus on standard of care (SOC) therapies.
Materials and Methods: ACE2 (n=107), TMPRSS2 and FURIN (n=38) protein expression was determined by immunohistochemical (IHC) analysis in NSCLC patients. sACE2 (n=64) were determined in lung cancer patients collected before, during or after treatment with SOC therapies. Finally, ACE2 protein expression was studied in Calu-3 lung cancer spheroids following treatment with SOC therapies.
Results: Membranous (m)ACE2 was co-expressed with mFURIN and/or mTMPRSS2 in 16% of the NSCLC samples and limited to the adenocarcinoma subtype. TMPRSS2 showed predominantly atypical cytoplasmic expression. mACE2 and sACE2 was more frequently expressed in mutant EGFR patients, but not mutant KRAS patients. Similarly, ACE2 mRNA expression was increased in EGFR mutant TCGA LUAD tumors and positively correlated with ERBB2-4 expression, while ACE2 expression was lower in KRAS mutant patients and inversely correlated with KRAS, NRAS and HRAS expression levels. Importantly, neoadjuvant chemotherapy was not associated with increased mACE2 expression levels. A significant difference was observed in sACE2 for patients treated with targeted therapies, but not for chemo- and immunotherapy. Finally, paradoxical MAPK activation by Dabrafenib, and Buparlisib- and Crizotinib-dependent PI3K inhibition reduced ACE2 expression in Calu-3 lung cancer spheroids.
Conclusion: We identified a role for mutation dependent PI3K pathway activation in the expression of mACE2 on NSCLC cells, associated with increased sACE2 levels in patients. Therefore, it is of high interest to study SARS-CoV-2 infected EGFR, ALK, ROS1 and cMET mutated NSCLC patients more in depth to get a better understanding on how mACE2, sACE2 and SOC TKIs can affect the course of COVID-19.
Note:
Funding Information: This was work supported by two “Kom Op Tegen Kanker” grants (ref 000100470, KotK_UA/2020/12228/1), a “Bijzonder Onderzoeksfonds COVID19-Project” grant (project ID: 42839) and a UZA Foundation grant.
Conflict of Interests: The authors declare no conflict of interest.
Ethical Approval: This retrospective study has been approved by the Ethics Committee of the Antwerp University Hospital/University of Antwerp (EC number 20/22/278).
Keywords: SARS-CoV-2, ACE2, Lung cancer
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