Medicina

Mammalian Target of Rapamycin: Discovery of Rapamycin Reveals a Signaling Pathway Important for Normal and Cancer Cell Growth
James J. Gibbons, Robert T. Abraham, and Ker Yu
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 signalingfunctions, 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 ofthe 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 inboth 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 otherpathways 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. Semin Oncol 36 (Suppl 3):S3-S17. © 2009 Published by Elsevier Inc.

n 1975, Suren Sehgal andcolleagues isolated a natural product with antifungal and immunosuppressive properties from a strain of Streptomyces found in a soil sample collected on Easter Island.1 The natural product drug was named rapamycin for Rapa Nui, the native name for the island. Rapamycin was shown to inhibit T-lymphocyte proliferation2 and proved to be a

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Pfizer Inc, Pearl River, NY. STATEMENT OF CONFLICT OFINTEREST: At the time this supplement was prepared, Drs Gibbons, Abraham, and Yu were employees of Wyeth Research, which was acquired by Pfizer Inc in October 2009. Address correspondence to James J. Gibbons, PhD, Pfizer Inc, Department of Oncology Discovery, 401 N Middletown Rd, Pearl River, NY 10960. E-mail: gibbonj@wyeth.com 0270-9295/09/$ - see front matter © 2009 Published by Elsevier Inc.doi:10.1053/j.seminoncol.2009.10.011

powerful tool in differentiating pathways that control T-cell proliferation through the interleukin-2 (IL-2) receptor from those controlling activation through the T-cell receptor.3,4 While the functional effects of rapamycin on T cells were being defined, the target of rapamycin (mechanism of action) remained a mystery. Researchers found the solution in 1991, using agene complementation approach in budding yeast strains selected for resistance to rapamycin to clone a gene whose protein product restored sensitivity to the drug. They named the gene TOR for “target of rapamycin.”5 Shortly thereafter, several groups independently cloned the mammalian homolog of TOR, most commonly referred to today as mTOR for “mammalian target of rapamycin.”6 –9 Rapamycin...