Ramucirumab is approved both as monotherapy and in combination with paclitaxel for advanced gastric cancer in patients with disease progression after chemotherapy. in tumor cells, the VeGfA-VEGFR2 binding activates autocrine survival and migration signaling in angiogenesis independent manner. the present in vitro study investigated the effects of single and combined treatments with Ramucirumab and paclitaxel on cell growth and migration highlighting the mechanisms underlying the interaction between the two drugs in gastric cancer cells. cell growth and motility were investigated in human gastric cancer cell lines characterized by different tumorigenicity. The inhibitory effect on cell growth exerted by both drugs was potentiated by their combination and was synergistic. Ramucirumab was able to enhance the inhibitory effect exerted by Paclitaxel on cell cycle progression. A synergistic action was also observed in the expression of proteins crucial for cell motility, microtubule organization and epithelial-mesenchymal transition. Furthermore, synergistic inhibition of VEGFR2 expression was obtained by the drug combination. These findings highlighted the importance of the combined treatment to strongly inhibit all the main molecules of both PI3K/Akt/mTOR and MAPK pathways thus preventing possible reactivations due to cross-talk phenomena. The combined treatment with Ramucirumab seems to be a promising option to overcome the paclitaxel resistance.VEGFR2 plays a crucial role in gastric cancer pathogenesis and progression and Ramucirumab (Ram), a monoclonal antibody against VEGFR2, is the first antiangiogenic agent with demonstrated activity against advanced gastric cancer. Based on the results obtained by two different phase III studies, Ram is approved both as monotherapy and in combination with Paclitaxel (PTX) for this malignancy in patients with disease in progression after a preceding therapy based on platinum and fluoropyrimidin 1-5 .The proangiogenic actions of VEGFs in endothelial cells are mediated primarily through the binding and activation of VEGFR2 6 and retrospective studies considered VEGF and its receptors as possible biomarkers in gastric carcinoma 7-9 . Moreover, the recent discovery of the production of different VEGF ligands and of the expression of VEGFR1, VEGFR2 and VEGFR3 in epithelial cancer cells, suggests a direct role for these ligands and their receptors in the autocrine control of some biological processes. In epithelial tumor cells, the binding of VEGFA, the main ligand of VEGFR2, activates downstream survival and migration signaling pathways represented by PI3K/ Akt/mTOR and MAPK cascades in a cell autonomous and angiogenesis independent manner 10-13 .The combined treatment with Ram seems to be a promising option to prevent the resistance to PTX also in recurrent and metastatic gastric cancer patients receiving taxane-based first-line palliative chemotherapy 14 . PTX is known to interfere with microtubule architecture by binding to β-tubulin, thereby blocking cell cycle progression at th...