Effect of mTOR Inhibitors in Nude Mice with Endometrial Carcinoma and Variable PTEN Expression Status

Background: The aim of this study was to investigate the sensitivity to rapamycin of endometrial cancer cells with different phosphatase and tensin homologue (PTEN) expression to understand the mechanism of resistance to mammalian target of rapamycin (mTOR) inhibitors in the treatment of endometrial cancer.
Material and Methods: Twenty specific pathogen-free female BALB/c mice received transplants of either HEC-1A (PTEN-positive) or Ishikawa (PTEN-negative) cells. Mice in the treatment group were injected intraperitoneally once a week for 4 consecutive weeks. The control group was injected weekly with phosphate buffer saline (PBS) for 4 consecutive weeks. Tumor volume, tumor mass, growth curves, and inhibition rate were measured, after which the mice were killed.

Results: Both tumor growth rate and size were slower in the treatment group than in the control group for all mice that received transplants of either HEC-1A or Ishikawa cells. The tumor inhibition rates in the treatment group were 48.1% and 67.1% in mice transplanted with HEC-1A and Ishikawa cells, respectively.
Conclusions: The inhibitory effects of rapamycin were enhanced in PTEN-negative Ishikawa tumor cells compared with PTEN-positive HEC-1A cells, which could explain the reduced effect of rapalogues in some endometrial cancer patients and help to understand the mechanism of resistance to this drug.

Keywords: Cell Proliferation - drug effects, Cell Line, Tumor, Animals, Endometrial Neoplasms - pathology, Green Fluorescent Proteins - metabolism, Luminescent Measurements, Mice, Inbred BALB C, Mice, Nude, Microscopy, Fluorescence, PTEN Phosphohydrolase - metabolism, Protein Kinase Inhibitors - therapeutic use, Sirolimus, TOR Serine-Threonine Kinases - metabolism, Xenograft Model Antitumor Assays