Abstract
<div>Abstract<p><b>Purpose:</b> In this study, we tested the antitumor activity of the dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor BEZ235 against gastric cancer <i>in vitro</i> and <i>in vivo</i>.</p><p><b>Experimental Design:</b> Gastric cancer cell lines (N87, MKN45, and MKN28) were incubated with BEZ235 and assessed for cell viability, cell cycle, and PI3K/mTOR target inhibition. <i>In vivo</i>, athymic nude mice were inoculated with N87, MKN28, or MKN45 cells and treated daily with BEZ235. 3′-Deoxy-3′-[<sup>18</sup>F]fluorothymidine ([<sup>18</sup>F]FLT) uptake was measured via small animal positron emission tomography (PET).</p><p><b>Results:</b><i>In vitro</i>, BEZ235 dose dependently decreased the cell viability of gastric cancer cell lines. The antiproliferative activity of BEZ235 was linked to a G<sub>1</sub> cell-cycle arrest. <i>In vivo</i>, BEZ235 treatment resulted in PI3K/mTOR target inhibition as shown by dephosphorylation of AKT and S6 protein in all xenograft models. However, BEZ235 treatment only inhibited tumor growth of N87 xenografts, whereas no antitumor effect was observed in the MKN28 and MKN45 xenograft models. Sensitivity to BEZ235 <i>in vivo</i> correlated with downregulation of the proliferation marker thymidine kinase 1. Accordingly, [<sup>18</sup>F]FLT uptake was only significantly reduced in the BEZ235-sensitive N87 xenograft model as measured by PET.</p><p><b>Conclusion:</b> In conclusion, <i>in vivo</i> sensitivity of gastric cancer xenografts to BEZ235 did not correlate with <i>in vitro</i> antiproliferative activity or <i>in vivo</i> PI3K/mTOR target inhibition by BEZ235. In contrast, [<sup>18</sup>F]FLT uptake was linked to BEZ235 <i>in vivo</i> sensitivity. Noninvasive [<sup>18</sup>F]FLT PET imaging might qualify as a novel marker for optimizing future clinical testing of dual PI3K/mTOR inhibitors. <i>Clin Cancer Res; 17(16); 5322–32. ©2011 AACR</i>.</p></div>
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