Temsirolimus (Torisel, Wyeth Pharmaceuticals) is an inhibitor of mammalian target of rapamycin (mTOR), a molecule implicated in multiple tumor-promoting intracellular signaling pathways. Temsirolimus recently became the first Food and Drug Administration–approved mTOR-targeted agent based on a phase III trial showing an overall survival advantage over IFN-a monotherapy in advanced renal cell carcinoma (RCC) patients with multiple adverse risk features (1). Temsirolimus is a soluble ester of rapamycin, a natural product that was initially developed as an antifungal drug and then as an immunosuppressive agent, with anticancer activity noted more than 20 years ago. Rapamycin (sirolimus, Rapamune) was isolated from the soil bacteria Streptomyces hygroscopicus found on Rapa Nui (commonly known as Easter Island) in the South Pacific in 1975, but its development for cancer therapeutics was not prioritized. The immunosuppressant effects of rapamycin were pursued and resulted in Food and Drug Administration approval in 1999 for prevention of renal allograft rejection. Laboratory studies of rapamycin starting in the early 1980s showed antitumor effects in several solid tumors. Cell cycle inhibitor-779 (now known as temsirolimus), a derivative of rapamycin, was identified in the 1990s and subsequently developed as an anticancer agent (2). mTOR, also known as rapamycin-associated protein, rapamycin target, or sirolimus effector protein, is a molecule implicated in multiple tumor-promoting intracellular signaling pathways (Fig. 1). mTOR is a 289-kDa serine/threonine-specific kinase with highly conserved structure. It exists in cytoplasm in a complex with three peptides: regulatory-associated protein of mTOR (raptor), mLST8, and GhL. Regulation of mTOR pathway activation is mediated through a series of complex signaling interactions linking growth factor receptor signaling and other cell stimuli, phosphatidylinositol 3-kinase activation, and activation of the Akt/protein kinase B pathway. Two distinct pathways have effects on cell cycle regulation downstream of mTOR. mTOR phosphorylates and activates p70 S6 kinase, leading to enhanced translation of certain ribosomal proteins and elongation factors. This process leads, among other effects, to the production of hypoxia-inducible factor-1a, which regulates the transcription of genes that stimulate cell growth and angiogenesis, including VEGF. Indeed, it has been shown that mTOR inhibition leads to RCC cell line and xenograft tumor growth inhibition, and this effect is mediated by hypoxiainducible factor (3). The second major mTOR effect is on the 4E-binding protein-1 and eukaryotic initiation factor-4 subunit E complex. Activated mTOR phosphorylates 4E-binding protein-1, promoting dissociation of this complex and allowing eukaryotic initiation factor-4 subunit E to stimulate an increase in the translation of mRNAs that encode cell cycle regulators, such as c-myc, cyclin D1, and ornithine decarboxylase. mTOR inhibition results in a block of 4E-binding protein-1 phosphorylation, sequestration of eukaryotic initiation factor-4 subunit E, and failure to form the complex required for translation. Inhibition of mTOR by temsirolimus requires a specific binding complex. Temsirolimus forms this complex with the FK506-binding protein and prohibits the activation of mTOR. This mechanism of action is similar for sirolimus, a temsirolimus metabolite, and both are likely responsible for inhibition of mTOR and antitumor effects after administration of temsirolimus. Temsirolimus/FK506-binding protein affects only one subpopulation of mTOR proteins, which reside in a multiprotein complex termed mTORC1. An …