Abstract
The mammalian target of rapamycin (mTOR) inhibitors, such as rapalogues, are a promising new tool for the treatment of metastatic gastroenteropancreatic endocrine tumors. However, their mechanisms of action remain to be established. We used two murine intestinal endocrine tumoral cell lines, STC-1 and GLUTag, to evaluate the antitumor effects of rapamycin in vitro and in vivo in a preclinical model of liver endocrine metastases. In vitro, rapamycin inhibited the proliferation of cells in the basal state and after stimulation by insulin-like growth factor-1. Simultaneously, p70S6 kinase and 4EBP1 phosphorylation was inhibited. In vivo, rapamycin substantially inhibited the intrahepatic growth of STC-1 cells, irrespectively of the timing of its administration and even when the treatment was administered after cell intrahepatic engraftment. In addition, treated animals had significantly prolonged survival (mean survival time: 47.7 days in treated animals versus 31.8 days in controls) and better clinical status. Rapamycin treatment was associated with a significant decrease in mitotic index and in intratumoral vascular density within STC-1 tumors. Furthermore, the antitumoral effect obtained after treatment with a combination of rapamycin and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 was more significant than with rapamycin alone in both cell lines. Our results suggest that the antitumor efficacy of rapamycin in neuroendocrine tumors results from a combination of antiproliferative and antiangiogenic effects. Interestingly, a more potent antitumor efficiency could be obtained by simultaneously targeting several levels of the PI3K/mTOR pathway.