4539 Background: The Target of Rapamycin (mTOR) pathway is upregulated in many human cancers, through activation of downstream targets such as AKT and HIF. Pre-clinical data suggests that agents targeting this pathway may be more effective in PTEN null tumors. Studies of agents targeting the mTOR pathway in RCC have shown frequent disease stabilization but relatively few objective responses. The aim of this study was to characterize the mTOR pathway in RCC by immunohistochemistry (IHC), and to determine its utility in selecting patients for agents targeting the mTOR pathway. Methods: An RCC tissue microarray containing specimens for 417 patients was subjected to IHC with antibodies against PTEN, pAKT, pS6, p27, and HIF1 alpha. The original tumors were staged according to the 1997 TNM, graded according to Fuhrman, and histologically subtyped according to the recommendations of the UICC. IHC expression was analyzed according to tumor type, stage, and grade. Pearson correlation analyses were used to determine the relationships between markers. Results: Loss of PTEN was increased in all RCC compared to normal, with the greatest loss occurring in Clear Cell Tumors (24.8%) and tumors having sarcomatoid features (34.4%). pAKT staining frequency was greatest in Collecting Duct (88.9%) followed by Clear Cell (57.5%), suggesting pathways of AKT activation other than PTEN loss. S6 kinase was highly expressed by sarcomatoid (61.1%) and Clear Cell tumors (40.8%) and was expressed more in high grade (73% vs. 31%) and high stage (50% vs 30%) tumors. Expression of HIF1 was highest in Clear Cell, but at only 25% positivity. PTEN expression was correlated with pAKT (p=0.028) and HIF expression (p<0.0001). Conclusions: IHC analysis suggest that not all RCC tumor types are equally amenable to treatment strategies targeting the mTOR pathway, but that a majority of patients have at least one component of the mTOR pathway impacted. Furthermore, the results suggest the mTOR pathway is more significantly altered in high grade tumors and tumors with poor prognostic features. Further evaluation is needed to assess the relationship of IHC results and clinical response, which could result in better patient selection. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth