Validating the effect of anti-angiogenic treatment on tumor cell invasion and metastasis in NSCLC
Final Report Abstract
Anti-angiogenic treatment targeting VEGF-VEGFR2 signaling has shown limited efficacy in lung cancer patients. Here, we demonstrate that inhibition of VEGFR2 in tumor cells – which is expressed in around 20% of NSCLC patients – leads to a proinvasive phenotype. Druginduced inhibition of tumor VEGFR2 releases a newly identified 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.
Publications
- (2018) Combined VEGF and PD-L1 Blockade Displays Synergistic Treatment Effects in an Autochthonous Mouse Model of Small Cell Lung Cancer. Cancer research 78 (15) 4270–4281
Meder, Lydia; Schuldt, Philipp; Thelen, Martin; Schmitt, Anna; Dietlein, Felix; Klein, Sebastian; Borchmann, Sven; Wennhold, Kerstin; Vlasic, Ignacija; Oberbeck, Sebastian; Riedel, Richard; Florin, Alexandra; Golfmann, Kristina; Schlößer, Hans A.; Odentha
(See online at https://doi.org/10.1158/0008-5472.CAN-17-2176) - (2018) LIN28B enhanced tumorigenesis in an autochthonous KRASG12V-driven lung carcinoma mouse model. Oncogene 37 (20) 2746–2756
Meder, Lydia; König, Katharina; Dietlein, Felix; Macheleidt, Iris; Florin, Alexandra; Ercanoglu, Meryem S.; Rommerscheidt-Fuss, Ursula; Koker, Mirjam; Schön, Gisela; Odenthal, Margarete; Klein, Florian; Büttner, Reinhard; Schulte, Johannes H.; Heukamp, Lu
(See online at https://doi.org/10.1038/s41388-018-0158-7) - (2018): Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1-amplified breast cancer. In: Oncogene 37 (42), S. 5682–5693
Golfmann K, Meder L, Tharun L, Malchers F, Koker M, Büttner R, Rosen N, Rodrik- Outmezguine V, and Ullrich RT
(See online at https://doi.org/10.1038/s41388-018-0380-3)
