key: cord-276548-bh3w7oas
authors: Ramkumar, K.; Stewart, C. A.; Gay, C.; Cardnell, R.; Diao, L.; Wang, Q.; Shen, L.; Xi, Y.; Kundu, S.; Della Corte, C.; Gibbons, D.; Wang, J.; Heymach, J. V.; Byers, L. A.
title: Elevated AXL expression following SARS-CoV-2 infection in non-small cell lung cancer
date: 2020-09-30
journal: Annals of Oncology
DOI: 10.1016/j.annonc.2020.08.1800
sha: 
doc_id: 276548
cord_uid: bh3w7oas

nan

We identified 94 patients with cancer and 226 patients without cancer. In univariate analysis, age, South Asian ethnicity and co-morbidities predicted mortality (see table) . More in the cancer cohort had died compared to the non-cancer cohort (43.6% vs 34.1%). The higher mortality among cancer patients was statistically significant among those aged 70 years and above (OR 2.28, 1.14-4.50, p ¼ 0.02). After adjusting for age, ethnicity and co-morbidities, a history of cancer was an independent predictor of mortality following COVID-19 (HR 1.57, 95% CI:1.04-2.4, p ¼ 0.03). Patients with active malignancy also had similarly increased adjusted mortality (HR 1.64, 95% CI: 1.03 e 2.6, p ¼ 0.04). Increasing age (HR 1.49 every 10 years, 95% CI:1.25-1.8, p <0.001), South Asian ethnicity (HR 2.92, 95% CI:1.73-4.9, p <0.001) and cerebrovascular disease (HR 1.93, 95% CI:1.18-3.2, p ¼ 0.008) were also confirmed as independent predictors of mortality.

Conclusions: Along with known risk factors, cancer confers an independent risk for mortality in COVID-19. Taken together, our findings support the need to continue 'shielding' patients with cancer from exposure to COVID-19 infection. Increasing age and co-morbidity should take precedence when weighing up risk factors for severe COVID-19 infection in cancer patients. Background: SARS-CoV-2 infection is the cause of the respiratory illness COVID-19, which presents most frequently with respiratory symptoms. SARS-CoV-2 cell entry requires interactions with ACE2 and TMPRSS2 on the surface of the host cell. Cancer patients and, specifically, those with thoracic malignancies seem to experience poorer clinical outcomes.

We utilized bulk and single-cell transcriptional data from a combination of normal and malignant tissues and cells from aerodigestive and respiratory tracts to explore mechanisms governing the expression of ACE2 and TMPRSS2. Additionally, we determined the effect of EMT induction, ZEB1 modulation, and SARS-CoV-2 infection on ACE2 expression.

Our bulk data suggests that aerodigestive and lung cancer models express a broad range of ACE2 and TMRPSS2, particularly in epithelial cells, and would serve as good models for studying SARS-CoV-2 infection. We assessed the relationship between ACE2 and epithelial differentiation in numerous datasets, and found consistent positive correlations with transcriptional and microRNA signifiers of epithelial differentiation. The miR-200 family e zinc finger E-box-binding homeobox 1 (ZEB1) pathway, which is an established regulator of EMT, also directly regulates ACE2 expression, likely via putative ZEB1 repressor sites located in the ACE2 promoter. Furthermore, SARS-CoV-2 infection reduces ACE2 expression and shifts cells to a more mesenchymal phenotype with loss of EPCAM and upregulation of ZEB1 and other EMT-associated genes.

Conclusions: ACE2-positive cells are almost exclusively epithelial and unexpectedly rare, considering the devastating impact of this infection. Following viral entry, SARS-CoV-2 infection induces molecular changes within the cells that are reminiscent of EMT, including increased ZEB1. ZEB1, in turn, appears to directly repress the expression of ACE2. This SARS-CoV-2-induced ACE2 deficiency, compounded by the downregulation of genes, including claudins, which play a critical role in restricting epithelial and endothelial permeability, exposes respiratory cells to increased risk of edema and acute respiratory distress syndrome (ARDS).

Legal entity responsible for the study: The authors. Methods: We analyzed mRNA expression of AXL and other TAM family members as well as angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, in treatment-naïve (n¼1016) and previously treated (n¼239) NSCLC tumors and in a panel of NSCLC cell lines (n¼70). We also analyzed AXL mRNA levels in NSCLC cell lines (n¼3) infected with SARS-CoV-2.

Results: In treatment-naïve and previously-treated NSCLC tumors, AXL mRNA expression was higher in mesenchymal tumors, as expected, and inversely correlated with ACE2. Similarly, in NSCLC cell lines, high ACE2 expression was associated with low AXL mRNA and protein expression. Notably, expression of ACE2 was downregulated while that of AXL and ZEB1, an EMT transcription factor, were upregulated in NSCLC cells infected with SARS-CoV-2 as compared to mock infected cells, suggesting a shift to a more mesenchymal phenotype. Treatment with bemcentinib for 24h downregulated ZEB1 expression in mesenchymal cell lines, reversing EMT.

Conclusions: These data, in the context of ACE2's role in preventing acute respiratory distress syndrome, suggest a shift from ACE2-expressing epithelial cells to a more mesenchymal phenotype characterized by low ACE2 and high AXL expression, upon infection of NSCLC cells with SARS-CoV-2. In addition to bemcentinib's antiviral activity, it can also reverse EMT, further supporting AXL and EMT as novel therapeutic targets for COVID-19 treatment.

Legal entity responsible for the study: Lauren A. Byers.

Background: COVID-19 pandemic presented serious challenge to oncology care due to the associated risks form infection and from disruption of care delivery. Therefore, many professional societies published recommendations to help manage cancer care during the crisis. The objective of our study was to assess the national responses of MENA countries in terms of publishing relevant guidelines and analyse various components of these guidelines. Conclusions: There is inconsistency in the components of the guidelines across the region, which may reflect the evolving nature of the pandemic and lack of clear evidence for many issues in question. There is a need from clear framework on essential components to be included in the guidelines to assure providing the best guidance to the oncology community.

Editorial acknowledgement: On behalf of the International Research Network on COVID-19 Impact on Cancer Care (IRN-CICC).

Legal entity responsible for the study: The authors. 

), through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program

Research grant/Funding (self): AstraZeneca. D. Gibbons: Advisory/Consultancy, Research grant/Funding (self

Advisory/Consultancy: Sanofi

Research grant/Funding (self): Janssen; Research grant/ Funding (self): Takeda; Research grant/Funding (self): Ribon Therapeutics; Research grant/Funding (self): Astellas

Boehringer Ingelheim; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Genentech

Research grant/Funding (self): GlaxoSmithKline

Advisory/Consultancy: Guardant Health

Advisory/Consultancy: Lilly; Advisory/ Consultancy: Novartis

Research grant/Funding (self), Licensing/Royalties: Spectrum

Advisory/Consultancy: Synta; Research grant/Funding (self): Bayer. L.A. Byers: Advisory/Consultancy, Research grant/Funding (self

Advisory/Consultancy: BergenBio; Pharma Mar SA; Merck

Bristol Myers Squibb; Genentech; Pfizer; Research grant/Funding (self): Tolero Pharmaceuticals. All other authors have declared no conflicts of interest

1737P National approaches to managing cancer care: Responses of countries in the MENA region to COVID-19 pandemic

United Arab Emirates; 6 Medical Oncology