Elevated AXL expression following SARS-CoV-2 infection in non-small cell lung cancer

ABSTRACT

Background: Patients with thoracic cancers affected by the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appear to have poor clinical outcomes. AXL, a TAM (Tyro3, AXL, Mer) family receptor tyrosine kinase, is a known mediator of epithelial to mesenchymal transition (EMT) and therapeutic resistance in non-small cell lung cancer (NSCLC) and other cancers. Additionally, AXL plays a role in efficient Ebola and Zika viral entry and infection and AXL inhibition has demonstrated antiviral activities. Recently, bemcentinib, a highly selective and potent AXL inhibitor with antiviral activity, has been fast-tracked as the first potential treatment for assessment in the United Kingdom’s ACcelerating COVID-19 Research & Development (ACCORD) multicenter, randomized phase II trial. 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 (n=1016) and previously treated (n=239) NSCLC tumors and in a panel of NSCLC cell lines (n=70). We also analyzed AXL mRNA levels in NSCLC cell lines (n=3) 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. Funding: NIH/NCI CCSG P30-CA016672 (Bioinformatics Shared Resource), NIH/NCI T32 CA009666, ASCO Young Investigator Award (C.M.G.);University of Texas SPORE in Lung Cancer P5-CA070907 (L.A.B. C.M.G.), NIH/NCI R01-CA207295, NIH/NCI U01-CA213273, the Department of Defense (LC170171) (L.A.B.), The LUNGevity foundation (D.G., L.A.B.), through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (J.V.H., J.W., L.A.B.);an Andrew Sabin Family Fellowship (L.A.B.), and The Rexanna Foundation for Fighting Lung Cancer (J.V.H., L.A.B.). Disclosure C. Gay Research grant/Funding (self) AstraZeneca. D. Gibbons Advisory/Consultancy, Research grant/Funding (self) AstraZeneca;Advisory/Consultancy GlaxoSmithKline;Advisory/Consultancy Sanofi;Advisory/Consultancy, Research grant/Funding (self) Janssen;Research grant/Funding (self) Takeda;Research grant/Funding (self) Ribon Therapeutics;Research grant/Funding (self) Astellas. J.V. Heymach Advisory/Consultancy, Research grant/Funding (self) AstraZeneca;Advisory/Consultancy Boehringer Ingelheim;Advisory/Consultancy Exelixis;Advisory/Consultancy Genentech;Advisory/Consultancy, Research grant/Funding (self) GlaxoSmithKline;Advisory/Consultancy Guardant Health;Advisory/Consultancy Hengrui;Advisory/Consultancy Lilly;Advisory/Consultancy Novartis;Advisory/Consultancy, Research grant/Funding (self), Licensing/Royalties Spectrum;Advisory/Consultancy EMD Serono;Advisory/Consultancy Synta;Research grant/Funding (self) Bayer. L.A. Byers Advisory/Consultancy, Research grant/Funding (self) AstraZeneca;AbbVie;GenMab;Sierra Oncology;Advisory/Consultancy BergenBio;Pharma Mar SA;Merck;Bristol Myers Squibb;G nentech;Pfizer;Research grant/Funding (self) Tolero Pharmaceuticals. All other authors have declared no conflicts of interest.