Gastric cancer growth control by BEZ235 in vivo does not correlate with PI3K/mTOR target inhibition but with [F]FLT uptake Running Title [F]FLT uptake correlates with BEZ235 activity

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Activation of the PI3K/mTOR pathway is a common event in gastric cancer and correlates with poor prognosis. PI3K/mTOR inhibition by the dual kinase inhibitor BEZ235 provides a novel and promising strategy for more effective treatment of gastric cancer patients. BEZ235 was recently reported to be well tolerated in a Phase I clinical study and inhibited S6 phosphorylation in tumor specimens. In the present study we demonstrate that PI3K/mTOR target inhibition by BEZ235 does not correlate with anti-tumor sensitivity in gastric cancer xenograft models. In contrast, [ 18 F]FLT PET uptake is linked to BEZ235 sensitivity in vivo. Our data suggest that the role of PI3K/mTOR target inhibition as a marker for dose finding and sensitivity to PI3K/mTOR inhibitors in translational studies should be reviewed. [ 18F ]FLT PET imaging might be considered for monitoring the activity of PI3K/mTOR inhibitors in future clinical trials. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose In the present study we tested the anti-tumor activity of the dual PI3K/mTOR inhibitor BEZ235 against gastric cancer in vitro and in vivo. Experimental design Gastric cancer cell lines (N87, MKN45, MKN28) were incubated with BEZ235 and assessed for cell viability, cell cycle and PI3K/mTOR target inhibition. In vivo, athymic nude mice were inoculated with N87, MKN28 or MKN45 cells and treated daily with BEZ235. [ 18 F]FLT uptake was measured via small-animal PET. Results In vitro, BEZ235 dose-dependently decreased the cell viability of gastric cancer cell lines. The anti-proliferative activity of BEZ235 was linked to a G1 cell cycle arrest. In vivo, BEZ235 treatment resulted in PI3K/mTOR target inhibition as demonstrated by dephosphorylation of AKT and S6 protein in all xenograft models. However, BEZ 235 treatment only inhibited tumor growth of N87 xenografts while no anti-tumor effect was observed in the MKN28 and MKN45 xenograft models. Sensitivity to BEZ235 in vivo correlated with downregulation of the proliferation marker thymidine kinase 1. Accordingly, [ 18 F]FLT uptake was only significantly reduced in the BEZ235 sensitive N87 xenograft model as measured by PET. Conclusion In conclusion, in vivo sensitivity of gastric cancer xenografts to BEZ235 did not correlate with in vitro anti-proliferative activity or in vivo PI3K/mTOR target inhibition by BEZ235. In contrast, [ 18 F]FLT uptake was linked to BEZ235 in vivo sensitivity. …