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

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. [Display omitted] •VEGFR2 inhibition in VEGFR2-positive NSCLC tumor cells induces tumor cell invasion•EphA2-S897 mediates invasive phenotype induced by VEGFR2 inhibition•These data provide a mechanism for the limited efficacy of VEGFR2-targeted therapy Anti-angiogenic treatment targeting VEGFR2 signaling has shown limited efficacy in lung cancer patients. Volz et al. show that VEGFR2 inhibition leads to a pro-invasive phenotype in VEGFR2-positive non-small cell lung cancer cells, which is mediated by phosphorylation of EphA2-S897.