Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany; Center for Molecular Medicine, Cologne, Germany.
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.
Cell Rep. 2020 Apr 28;31(4):107568. doi: 10.1016/j.celrep.2020.107568.
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.
针对血管内皮生长因子 (VEGF)-VEGFR2 信号的抗血管生成治疗在肺癌患者中的疗效有限。在这里，我们证明了在约 20%的非鳞状非小细胞肺癌 (NSCLC) 患者中表达的肿瘤细胞中 VEGFR2 的抑制作用导致侵袭表型。肿瘤 VEGFR2 的药物诱导抑制会干扰 EphA2/VEGFR2 异源复合物的形成，从而允许 RSK 与 EphA2 的丝氨酸 897 相互作用。RSK 的抑制减少 EphA2 的丝氨酸 897 磷酸化。EphA2 的丝氨酸 897 的选择性遗传建模或 EphA2 的抑制消除了 VEGFR2 抑制时体内转移的形成。总之，这些发现表明，VEGFR2 靶向治疗使 VEGFR2 阳性 NSCLC 对丝氨酸 897 EphA2 依赖性侵袭性肿瘤生长和转移敏感。这些数据揭示了解释 VEGFR2 靶向抗血管生成治疗在肺癌患者中疗效有限的分子机制。
