[Targeting Ras-PI3K/mTOR pathway and the predictive biomarkers in endometrial cancer]

The Ras-PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian Target of Rapamycin) pathway is frequently activated in various types of cancers. A number of inhibitors targeting the PI3K/mTOR pathway and MAPK pathway (another Ras effector pathway) are under development. PI3K/AKT activating mutations, including mutations in PTEN (50%), PIK3CA (30%), and K-Ras (20%), are frequently observed in endometrial cancer. A coexistence of these mutations is also commonly observed. We classified 13 endometrial cancer cell lines into three groups according to their mutational status in these genes: Group A (n=9); K-Ras wild-type and PTEN mutant, Group B (n=2); K-Ras mutant, and Group C (n=2) without any mutations in K-Ras, PTEN or PIK3CA. We determined the effects a dual PI3K/mTOR inhibitor (Inhibitor P) on these cell lines. MTT assay revealed that all the nine cell lines in Group A were sensitive to the inhibitor P (IC50<100 nM), whereas the other four cell lines in Group B or C were less sensitive to it(IC50>100 nM). Daily oral administration of inhibitor P showed anti-tumor effects in the mice bearing Group A tumors. Our data suggest that dual inhibition of the PI3K/mTOR is a promising molecular-targeted therapeutic for certain endometrial cancers, and that the mutational status of K-Ras and PI3K pathway-related genes, like PTEN and PIK3CA, could be useful for predicting sensitivities to such agents.