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

Volz C, Breid S, Selenz C, Zaplatina A, Golfmann K, Meder L, Dietlein F, Borchmann S, Chatterjee S, Siobal M, Schoettle J, Florin A, Koker M, Nill M, Ozretic L, Uhlenbrock N, Smith S, Buettner R, Miao H, Wang B, Reinhardt HC, Rauh D, Hallek M, Acker-Palmer A, Heukamp LC, Ullrich RT (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Cell Reports Elsevier (Cell Press)

Book Volume: 31

Article Number: 107568

Journal Issue: 4

DOI: 10.1016/j.celrep.2020.107568

Abstract

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.

Authors with CRIS profile

Lydia Meder

Involved external institutions

Universität zu Köln DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE) Case Western Reserve University US United States (USA) (US) Technische Universität Dortmund DE Germany (DE) Goethe-Universität Frankfurt am Main DE Germany (DE) Dres Tiemann & Schulte Partnerschaft Institut für Hämatopathologie Hamburg DE Germany (DE) Royal Free Hospital GB United Kingdom (GB)

How to cite

APA:

Volz, C., Breid, S., Selenz, C., Zaplatina, A., Golfmann, K., Meder, L.,... Ullrich, R.T. (2020). Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC. Cell Reports, 31(4). https://doi.org/10.1016/j.celrep.2020.107568

MLA:

Volz, Caroline, et al. "Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC." Cell Reports 31.4 (2020).

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