Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC.

Autor:	Volz C; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany., Breid S; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany., Selenz C; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany., Zaplatina A; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany., Golfmann K; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany., Meder L; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany., Dietlein F; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Cancer Program, Broad Institute of MIT and Harvard, US Institute for Pathology, Cambridge, MA, USA., Borchmann S; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany; University of Cologne, Department I of Internal Medicine, German Hodgkin Study Group (GHSG), Cologne, Germany; University of Cologne, Department I of Internal Medicine, Else Kröner Forschungskolleg Clonal Evolution in Cancer, Cologne, Germany., Chatterjee S; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany., Siobal M; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany., Schöttle J; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Department of Translational Genomics, University of Cologne, Medical Faculty, Cologne, Germany., Florin A; Institute of Pathology, University Hospital Medical School, Cologne, Germany., Koker M; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany., Nill M; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany., Ozretić L; Department of Cellular Pathology, Royal Free Hospital, London NW3 2QG, UK., Uhlenbrock N; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany., Smith S; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany., Büttner R; Institute of Pathology, University Hospital Medical School, Cologne, Germany., Miao H; Rammelkamp Center for Research, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Pharmacology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Wang B; Rammelkamp Center for Research, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Department of Pharmacology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH, USA., Reinhardt HC; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany., Rauh D; Faculty of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany., Hallek M; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany., Acker-Palmer A; Institute for Cell Biology and Neuroscience, University of Frankfurt, Frankfurt, Germany., Heukamp LC; Institute for Hematopathology Hamburg, Hamburg, Germany., Ullrich RT; Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany. Electronic address: roland.ullrich@uk-koeln.de.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2020 Apr 28; Vol. 31 (4), pp. 107568.
DOI:	10.1016/j.celrep.2020.107568
Abstrakt:	Anti-angiogenic treatment targeting vascular endothelial growth factor (VEGF)-VEGFR2 signaling has shown limited efficacy in lung cancer patients. Here, we demonstrate that inhibition of VEGFR2 in tumor cells, expressed in ∼20% of non-squamous non-small cell lung cancer (NSCLC) patients, leads to a pro-invasive phenotype. Drug-induced inhibition of tumor VEGFR2 interferes with the formation of the EphA2/VEGFR2 heterocomplex, thereby allowing RSK to interact with Serine 897 of EphA2. Inhibition of RSK decreases phosphorylation of Serine 897 EphA2. Selective genetic modeling of Serine 897 of EphA2 or inhibition of EphA2 abrogates the formation of metastases in vivo upon VEGFR2 inhibition. In summary, these findings demonstrate that VEGFR2-targeted therapy conditions VEGFR2-positive NSCLC to Serine 897 EphA2-dependent aggressive tumor growth and metastasis. These data shed light on the molecular mechanisms explaining the limited efficacy of VEGFR2-targeted anti-angiogenic treatment in lung cancer patients. Competing Interests: Declaration of Interests The authors declare no competing interests. (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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