Abstract 4470: The dual PI3K/mTOR inhibitor BEZ235 impairs gastric cancer growth in vitro and in vivo

Abstract

Abstract Background Gastric cancer is still a major health problem and the prognosis at advanced stage of disease with the current chemotherapeutic treatment strategies remains poor. Therefore novel treatment strategies and molecular targets for gastric cancer therapy are desperately needed. PI3K/mTOR pathway mutations, especially PTEN, PI3K3C and AKT mutations and pS6 overexpression, frequently occur in gastric cancer. Thus, we tested the activity of the dual PI3K and mTOR BEZ235 against gastric cancer in vitro and in vivo. Materials and Methods Three gastric cancer cell lines (N87, Mkn28 and MKN45) were treated with BEZ235 (20-80nM) and assessed for cell viability, cell death and cell cycle via celltiter blue and FACS analysis, respectively. PI3K/mTOR protein target modulation was measured by Western blotting. For in vivo studies athymic nude mice were inoculated with N87 or Mkn45 cells bilaterally and treated daily with 20 or 40mg/kg BEZ235. Results In vitro, treatment of gastric cancer cells with 20-80nM BEZ235 decreased cell growth in a dose dependent manner in all cell lines tested (up to −70%). This anti-proliferative activity was accompanied with a G1 cell cycle arrest of gastric cancer cells (up to 75%), whereas no significant levels of cell death were detected. On the molecular level, BEZ235 therapy resulted in a decrease of phosphorylation of AKT and S6 protein at 80nM. Notably, lower concentrations abolished mTOR downstream signalling but had no effect on AKT phosphorylation. In vivo, treatment with 20 and 40mg/kg BEZ235 resulted in a significant anti-tumor effect in a N87 gastric cancer xenograft mouse model. Interestingly, BEZ235 therapy displayed no anti-tumor activity in the MKN45 gastric cancer xenograft mouse model. In both models, we observed similar results in terms of PI3K/mTOR pathway downregulation in xenografts. Conclusion BEZ235 has pronounced anti-tumor activity in gastric cancer cells at low nanomolar range, which is linked with PI3K/mTOR downregulation and G1 cell cycle arrest. In vivo, N87 gastric cancer cells responded to BEZ235 treatment, whereas MKN45 cells were resistant. Thus, in our models in vitro sensitivity of BEZ235 did not predict for in vivo activity. We are currently conducting a microPET mouse study in order to evaluate whether PET is a suitable tool to predict BEZ235 sensitivity in vivo and the results will be presented at the meeting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4470.