PMID- 15010827 OWN - NLM STAT- MEDLINE DCOM- 20040416 LR - 20220330 IS - 1019-6439 (Print) IS - 1019-6439 (Linking) VI - 24 IP - 4 DP - 2004 Apr TI - Pharmacogenomic profiling of the PI3K/PTEN-AKT-mTOR pathway in common human tumors. PG - 893-900 AB - The protein synthetic machinery is activated by a variety of genetic alterations during tumor progression and represents an attractive target for cancer therapy. The mammalian target of rapamycin (mTOR) plays an important role in regulating protein translation through phosphorylation of p70 S6 kinase 1 (S6K1), a protein involved in ribosome biogenesis, and 4E-BP1 (eIF-4E binding protein), a translation repressor. It has been shown that mTOR has a direct linkage to the phosphatidylinositol-3'-kinase (PI3K)/PTEN-AKT survival pathway. Recent studies have demonstrated that mTOR inhibition by rapamycin or its analogues have remarkable activity against a wide range of human cancers in vitro and in human tumor xenograft models. Phase I clinical evaluations also suggested an anti-tumor effect of rapamycin analogue such as CCI-779. The clinical challenge for the application of this class of anticancer drug is the ability to prospectively identify which tumors will be sensitive to mTOR inhibition. Recent studies have identified cellular markers that are associated with the in vitro activity of rapamycin or CCI-779. However, there have been no reports on how these cellular markers are expressed together in human tumor specimen. In this study, multiple components of the PI3K/PTEN-AKT-mTOR pathway were evaluated by immunohistochemistry in tissue arrays containing 124 tumors from 8 common tumor types. The results show variable expression of all the signaling proteins. For example, mTOR expression was low in brain tumors, but high in the rest of tumors. High levels of 4E-BP1 were seen in colonic adenocarcinoma and low levels in lymphoma. Phospho-AKT (p-AKT) and phospho-S6K1 (p-S6K1) were the only proteins that had significantly correlated protein expression (rs=0.51, p<0.001). Since low PTEN, high p-AKT and high p-S6K1 expression render tumors sensitive to mTOR inhibition in vitro, these criteria were used to model tumor sensitivity. Overall, 26% of tumors (32/124) are predicted to be sensitive to mTOR inhibition, with variable rates for different tumors (melanoma 0% vs ovarian 41%). This is the first report on the PI3K/PTEN-AKT-mTOR pathway in common human tumors and evaluation of the coordinated expression of different signaling proteins. This study should provide a useful tool for selecting future targeted phase II and III clinical trials in the development of this exciting class of agents. FAU - Xu, Guang AU - Xu G AD - Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Zhang, Wanghai AU - Zhang W FAU - Bertram, Paula AU - Bertram P FAU - Zheng, Xiao Feng AU - Zheng XF FAU - McLeod, Howard AU - McLeod H LA - eng GR - P30 CA091842/CA/NCI NIH HHS/United States GR - U01 GM63340/GM/NIGMS NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, U.S. Gov't, P.H.S. PL - Greece TA - Int J Oncol JT - International journal of oncology JID - 9306042 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Carrier Proteins) RN - 0 (Cell Cycle Proteins) RN - 0 (EIF4EBP1 protein, human) RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Tumor Suppressor Proteins) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (AKT1 protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.1.3.2 (Phosphoric Monoester Hydrolases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) SB - IM MH - Adaptor Proteins, Signal Transducing MH - Carrier Proteins/genetics MH - Cell Cycle Proteins MH - *Gene Expression Profiling MH - Humans MH - Neoplasms/*genetics/pathology MH - PTEN Phosphohydrolase MH - Pharmacogenetics MH - Phosphatidylinositol 3-Kinases/*genetics MH - Phosphoproteins/genetics MH - Phosphoric Monoester Hydrolases/*genetics MH - Phosphorylation MH - Protein Kinases/*genetics MH - *Protein Serine-Threonine Kinases MH - Proto-Oncogene Proteins/*genetics MH - Proto-Oncogene Proteins c-akt MH - Ribosomal Protein S6 Kinases, 70-kDa/metabolism MH - Signal Transduction MH - TOR Serine-Threonine Kinases MH - Tumor Suppressor Proteins/*genetics EDAT- 2004/03/11 05:00 MHDA- 2004/04/17 05:00 CRDT- 2004/03/11 05:00 PHST- 2004/03/11 05:00 [pubmed] PHST- 2004/04/17 05:00 [medline] PHST- 2004/03/11 05:00 [entrez] PST - ppublish SO - Int J Oncol. 2004 Apr;24(4):893-900.