Volz, Caroline, Breid, Sara, Selenz, Carolin, Zaplatina, Alina, Golfmann, Kristina, Meder, Lydia, Dietlein, Felix, Borchmann, Sven, Chatterjee, Sampurna, Siobal, Maike, Schoettle, Jakob, Florin, Alexandra, Koker, Mirjam, Nill, Marieke, Ozretic, Luka, Uhlenbrock, Niklas, Smith, Steven, Buettner, Reinhard, Miao, Hui, Wang, Bingcheng, Reinhardt, H. Christian, Rauh, Daniel, Hallek, Michael, Acker-Palmer, Amparo, Heukamp, Lukas C. and Ullrich, Roland T. (2020). Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC. Cell Reports, 31 (4). CAMBRIDGE: CELL PRESS. ISSN 2211-1247

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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 similar to 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Volz, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Breid, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Selenz, CarolinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zaplatina, AlinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Golfmann, KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meder, LydiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dietlein, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borchmann, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chatterjee, SampurnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siobal, MaikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schoettle, JakobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Florin, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koker, MirjamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nill, MariekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ozretic, LukaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uhlenbrock, NiklasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smith, StevenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miao, HuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wang, BingchengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rauh, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Acker-Palmer, AmparoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, Roland T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-336292
DOI: 10.1016/j.celrep.2020.107568
Journal or Publication Title: Cell Reports
Volume: 31
Number: 4
Date: 2020
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 2211-1247
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ENDOTHELIAL GROWTH-FACTOR; ACQUIRED-RESISTANCE; MAMMALIAN TARGET; GENE-EXPRESSION; EPH RECEPTORS; IN-VIVO; ANGIOGENESIS; THERAPY; CANCER; PROGRESSIONMultiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33629

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