PTEN-deficient tumors show increased sensitivity to mTOR inhibition. This study demonstrates that pharmacologic inhibition of the mTOR pathway using CCl-779, a rapamycin derivative, effectively blocks the growth of PTEN-deficient cancer cells. In vitro and in vivo experiments with isogenic PTEN+/+ and PTEN-/- mouse cells, as well as human cancer cells with defined PTEN status, showed that PTEN-null cells were more sensitive to mTOR inhibition. This sensitivity was not due to differences in biochemical inhibition of the mTOR pathway, as S6 phosphorylation was inhibited in both sensitive and resistant cell lines. The study also found that loss of PTEN correlated with increased S6 kinase activity and phosphorylation of ribosomal S6 protein, indicating activation of the mTOR pathway in these cells. Additionally, constitutive activation of Akt in PTEN+/+ cells was reversed by CCl-779 treatment, suggesting that mTOR functions downstream of Akt in tumorigenesis. In vivo experiments with PTEN-deficient tumors in immunodeficient mice showed that CCl-779 completely blocked tumor growth, while PTEN+/+ tumors showed only partial inhibition. These results suggest that mTOR inhibitors may have clinical utility in human cancers lacking PTEN. The study also examined the effects of CCl-779 on tumor growth, apoptosis, and cell size, finding that it reduced tumor size, increased apoptosis, and inhibited mTOR signaling in PTEN-deficient tumors. The findings support the hypothesis that PTEN-deficient tumors are more sensitive to mTOR inhibition due to increased mTOR activity and Akt signaling. The study highlights the potential of mTOR inhibitors as a therapeutic strategy for PTEN-deficient cancers.PTEN-deficient tumors show increased sensitivity to mTOR inhibition. This study demonstrates that pharmacologic inhibition of the mTOR pathway using CCl-779, a rapamycin derivative, effectively blocks the growth of PTEN-deficient cancer cells. In vitro and in vivo experiments with isogenic PTEN+/+ and PTEN-/- mouse cells, as well as human cancer cells with defined PTEN status, showed that PTEN-null cells were more sensitive to mTOR inhibition. This sensitivity was not due to differences in biochemical inhibition of the mTOR pathway, as S6 phosphorylation was inhibited in both sensitive and resistant cell lines. The study also found that loss of PTEN correlated with increased S6 kinase activity and phosphorylation of ribosomal S6 protein, indicating activation of the mTOR pathway in these cells. Additionally, constitutive activation of Akt in PTEN+/+ cells was reversed by CCl-779 treatment, suggesting that mTOR functions downstream of Akt in tumorigenesis. In vivo experiments with PTEN-deficient tumors in immunodeficient mice showed that CCl-779 completely blocked tumor growth, while PTEN+/+ tumors showed only partial inhibition. These results suggest that mTOR inhibitors may have clinical utility in human cancers lacking PTEN. The study also examined the effects of CCl-779 on tumor growth, apoptosis, and cell size, finding that it reduced tumor size, increased apoptosis, and inhibited mTOR signaling in PTEN-deficient tumors. The findings support the hypothesis that PTEN-deficient tumors are more sensitive to mTOR inhibition due to increased mTOR activity and Akt signaling. The study highlights the potential of mTOR inhibitors as a therapeutic strategy for PTEN-deficient cancers.