The objective of this study was to analyze the expression levels of multiple 
components in the mammalian target of rapamycin (mTOR) signaling pathway in 
radical nephrectomy specimens from patients with metastatic renal-cell carcinoma 
(RCC) treated with mTOR inhibitors in order to identify factors predicting 
susceptibility to these agents. This study retrospectively included a total of 
48 consecutive patients undergoing radical nephrectomy, who were diagnosed with 
metastatic RCC and subsequently treated with an mTOR inhibitor (everolimus or 
temsirolimus) as either first- or second-line systemic therapy. Expression 
levels of 5 molecular markers involved in the signaling pathway associated with 
mTOR, including PTEN, phosphorylated (p)-Akt, p-mTOR, p-p70 ribosomal S6 kinase, 
and p-4E-binding protein 1 (4E-BP1), were measured by immunohistochemical 
staining of primary RCC specimens. Of several factors examined, bone metastasis, 
liver metastasis, and the expression level of p-4E-BP1 were shown to have 
significant impacts on the response to the mTOR inhibitors. Progression-free 
survival (PFS) was significantly correlated with the expression levels of PTEN 
and p-4E-BP1 in addition to the presence of bone metastasis on univariate 
analysis. Of these significant factors, p-4E-BP1 expression and bone metastasis 
appeared to be independently associated with PFS on multivariate analysis. These 
findings suggest that it would be useful to consider the expression levels of 
potential molecular markers in the mTOR signaling pathway, particularly 
p-4E-BP1, as well as conventional clinical parameters when selecting patients 
with metastatic RCC who are likely to benefit from treatment with mTOR 
inhibitors.