PROJECT SUMMARY (See instrjctions): We and others have demonstrated that the phosphatidylinositol-3-kinase (PI3K)/PTEN/AKT/mT0R pathway is activated in over 60% of endometrial cancers by mutations in the PTEN (30-50%), PIK3CA (20-40%), PIK3R1 (20%) and AKT1 (-2%) genes. Further, we and others have shown that the RAS/RAF pathway is activated by KRAS mutations in -20% of endometrial cancers. In contrast to other cancer types, none of these mutations are mutually exclusive and two or more thus frequently occur in the same endometrial tumor. We and others have also recently demonstrated that KRAS mutations predict a lack of response to PISK pathway-targeted therapies in cancer cells and vice versa. Thus, in this application, we will test the hypotheses in vitro and in vivo in endometrial cancer that: 1. PISK pathway-targeted drugs will be selectively active in tumors with mutations in the PISK pathway in the absence of KRAS mutations, 2. Specific aberrations in the PISK pathway will determine the response to targeting different nodes in the PISK pathway, 3. Aberrations in the RAS/RAF pathway in the absence of PISK pathway mutations will render tumors responsive to RAS/RAF-pathway targeted drugs (e.g. MEK inhibitors), and 4. Cells with coordinate mutations in both the PISK and RAS/RAF pathways will be resistant to PISK pathway inhibitors and MEK inhibitors alone but sensitive to concurrent targeting of both pathways. Our specific aims are thus: Aim 1: To determine effects of mutations in the PISK and RAS/RAF pathways on downstream signaling events and clinical correlates in endometrial cancer. Aim 2: To determine whether specific aberrations in the PISK and RAS/RAF pathways predict effects of targeting specific nodes in the PISK and RAS/RAF pathways. Aim 3: To identify and validate predictive and pharmacodynamic markers of antitumor efficacy for PISK- and RAS/RAF-targeted therapies in endometrial cancer. Aim 4: To determine whether predictive and pharmacodynamic markers indicate responsiveness to the dual PISK/mTOR inhibitor GSK2126458A in a phase II clinical trial in advanced endometrial cancer.