PMID- 19963098 OWN - NLM STAT- MEDLINE DCOM- 20100121 LR - 20211203 IS - 1532-8708 (Electronic) IS - 0093-7754 (Linking) VI - 36 Suppl 3 DP - 2009 Dec TI - Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth. PG - S3-S17 LID - 10.1053/j.seminoncol.2009.10.011 [doi] AB - Since the discovery of rapamycin, considerable progress has been made in unraveling the details of the mammalian target of rapamycin (mTOR) signaling network, including the upstream mechanisms that modulate mTOR signaling functions, and the roles of mTOR in the regulation of mRNA translation and other cell growth-related responses. mTOR is found in two different complexes within the cell, mTORC1 and mTORC2, but only mTORC1 is sensitive to inhibition by rapamycin. mTORC1 is a master controller of protein synthesis, integrating signals from growth factors within the context of the energy and nutritional conditions of the cell. Activated mTORC1 regulates protein synthesis by directly phosphorylating 4E-binding protein 1 (4E-BP1) and p70S6K (S6K), translation initiation factors that are important to cap-dependent mRNA translation, which increases the level of many proteins that are needed for cell cycle progression, proliferation, angiogenesis, and survival pathways. In normal physiology, the roles of mTOR in both glucose and lipid catabolism underscore the importance of the mTOR pathway in the production of metabolic energy in quantities sufficient to fuel cell growth and mitotic cell division. Several oncogenes and tumor-suppressor genes that activate mTORC1, often through the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, are frequently dysregulated in cancer. Novel analogs of rapamycin (temsirolimus, everolimus, and deforolimus), which have improved pharmaceutical properties, were designed for oncology indications. Clinical trials of these analogs have already validated the importance of mTOR inhibition as a novel treatment strategy for several malignancies. Inhibition of mTOR now represents an attractive anti-tumor target, either alone or in combination with strategies to target other pathways that may overcome resistance. The far-reaching downstream consequences of mTOR inhibition make defining the critical molecular effector mechanisms that mediate the anti-tumor response and associated biomarkers that predict responsiveness to mTOR inhibitors a challenge and priority for the field. FAU - Gibbons, James J AU - Gibbons JJ AD - Department of Oncology Discovery, Pfizer Inc., 401 N Middletown Rd., Pearl River, NY 10960, USA. gibbonj@wyeth.com FAU - Abraham, Robert T AU - Abraham RT FAU - Yu, Ker AU - Yu K LA - eng PT - Journal Article PT - Review PL - United States TA - Semin Oncol JT - Seminars in oncology JID - 0420432 RN - 0 (Antibiotics, Antineoplastic) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Antibiotics, Antineoplastic/chemical synthesis/isolation & purification/pharmacology/therapeutic use MH - Cell Proliferation/*drug effects MH - *Drug Discovery MH - Humans MH - Models, Biological MH - Neoplasms/drug therapy/genetics/metabolism/*pathology MH - Protein Biosynthesis/drug effects/genetics MH - Protein Kinases/metabolism/*physiology MH - Signal Transduction/drug effects/genetics/physiology MH - Sirolimus/chemical synthesis/isolation & purification/pharmacology/*therapeutic use MH - TOR Serine-Threonine Kinases RF - 171 EDAT- 2010/01/09 06:00 MHDA- 2010/01/22 06:00 CRDT- 2009/12/08 06:00 PHST- 2009/12/08 06:00 [entrez] PHST- 2010/01/09 06:00 [pubmed] PHST- 2010/01/22 06:00 [medline] AID - S0093-7754(09)00193-6 [pii] AID - 10.1053/j.seminoncol.2009.10.011 [doi] PST - ppublish SO - Semin Oncol. 2009 Dec;36 Suppl 3:S3-S17. doi: 10.1053/j.seminoncol.2009.10.011.