This includes elucidation of the functional significance of cytosolic binding of known GLUTinteracting proteins and the discovery of additional protein-protein interactions. Such applications may aid BAY-60-7550 efforts to identify means to improve diabetes treatment in the wider MG132 Proteasome inhibitor context of non-HIV associated insulin resistance. Constitutive activation of the PI3Kpathway results from various types of alterations, including changes to RTKs, Ras, PIK3CA, and PTEN. Endometrial cancer is the fourth most frequent cancer in women. There are two pathogenetic types of endometrial carcinomas: estrogendependent type Iand estrogenindependent type II. Approximately 80% of endometrial carcinomas are classified as type I. Mutations of K-Ras, PTEN, and PIK3CAare frequently observed in endometrial cancer. In addition, we previously revealed that chromosomal imbalances in the RasPI3K pathway genesare also common in endometrial cancer, indicating that the Ras-PI3K pathway is activated in the majority of endometrial cancers. Novel therapeutics targeting the PI3K/mTORpathway are being intensively developed. The first clinically approved inhibitors are rapamycin analogs, such as everolimusand temsirolimus, targeting the mTORC1 complex for use with advanced renal cell carcinomas. However, clinical trials with single-agent rapalog therapies have shown limited response rates in other cancer types. Several potent and selective PI3K inhibitors have recently entered earlyphase clinical trials for treatment of various malignant tumors. The limitation of the rapalogs might be explained by the activity of the mTORC1-independent substrates of Akt, including GSK3beta and FOXO1/3a. Rapalogs do not prevent mTORC2dependent phosphorylation of Akt on Ser-473 or PDK1-dependent phosphorylation of Akt on Thr-308. In addition, rapalogs may cause feedback activation of the PI3K-Akt pathway mediated by insulin-like growth factor-1 receptorsignaling. Therefore, a dual PI3K/mTOR inhibition might be a more rational therapeutic option than mTOR inhibition alone in tumors with PI3K-activating mutations. Developing predictive biomarkers of the PI3K/mTOR inhibitors is important; however, the existence of alterations in the PI3K pathwayalone is not necessarily a good biomarker for these compounds. Indeed, tumors with alterations in Ras and RTK do not respond sufficiently to simple PI3K pathway inhibition. Moreover, multiple genetic alterations in the RTK-Ras-PI3K pathway are reported in many cancers. It remains to be determined which types of alterations are useful as predictive biomarkers. In this study, we firstly evaluated the antitumor effect of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in a panel of endometrial cancer cell lines. Second, we analyzed the antitumor effect of NVP-BEZ235 and RAD001 in vivo. Third, we focused on the predictive biomarkers to the PI3K/mTOR inhibitors, using the mutational status of KRas, PTEN, and PIK3CA. Finally, we addressed the antitumor effect of the combined inhibition of the PI3K/mTOR and MAPK pathways in cells with K-Ras alterations. This manuscript includes clinical data, which were previously published elsewhere. The authors declare that all these participants provided written informed consent, and the study design was approved by the Institutional Review Board of the University of Tokyo Hospital. We examined activity of the PI3K/mTOR pathway inhibitors in endometrial cancer cell lines with a particular focus onthe antitumor effect of an mTOR inhibitorand a dual PI3K/mTOR inhibitor,predictive biomarkers of the mutational status of the PI3K pathway genes, andcombined inhibition of the MAPK pathway and the PI3K/ mTOR pathway in K-Ras mutant cells.