Abstract
In this study, we tested the antitumor activity of the dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor BEZ235 against gastric cancer in vitro and in vivo. Gastric cancer cell lines (N87, MKN45, and 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. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake was measured via small animal positron emission tomography (PET). In vitro, BEZ235 dose dependently decreased the cell viability of gastric cancer cell lines. The antiproliferative activity of BEZ235 was linked to a G(1) cell-cycle arrest. In vivo, 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 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. In conclusion, in vivo sensitivity of gastric cancer xenografts to BEZ235 did not correlate with in vitro antiproliferative activity or in vivo PI3K/mTOR target inhibition by BEZ235. In contrast, [(18)F]FLT uptake was linked to BEZ235 in vivo sensitivity. Noninvasive [(18)F]FLT PET imaging might qualify as a novel marker for optimizing future clinical testing of dual PI3K/mTOR inhibitors.
Highlights
Gastric cancer, declining in incidence, is still a leading cause of cancer-related deaths worldwide [1, 2]
BEZ235 treatment resulted in phosphoinositide 3-kinase (PI3K)/mTOR target inhibition as shown by dephosphorylation of AKT and S6 protein in all xenograft models
BEZ235 treatment only inhibited tumor growth of N87 xenografts, whereas no antitumor effect was observed in the MKN28 and MKN45 xenograft models
Summary
Declining in incidence, is still a leading cause of cancer-related deaths worldwide [1, 2]. The PI3K pathway is frequently activated constitutively because of mutations of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), PI3K3C, and AKT [7,8,9]. The biological relevance of this signal transduction pathway is highlighted by the fact that the loss of PTEN heterozygosity serves as an independent prognostic factor in gastric cancer [10, 11]. The PI3K/AKT downstream target mTOR is a relevant molecular target for antitumor therapy including gastric cancer [12,13,14]. Our group has recently showed that mTOR inhibition by the mTOR complex (mTORC) 1 inhibitor everolimus impairs gastric cancer growth in vitro and leads to sustained tumor growth control in vivo [12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
