Review 10.1586/14737140.8.2.283 © 2008 Future Drugs Ltd ISSN 1473-7140 283 www.future-drugs.com mTOR pathway in renal cell carcinoma Expert Rev. Anticancer Ther. 8(2), 283–292 (2008) Sara C Hanna, Samuel A Heathcote and William Y Kim † † Author for correspondence Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB 7295, Chapel Hill, NC 27599, USA Tel.: +1 919 966 4765 Fax: +1 919 966 8212 wykim@med.unc.edu After decades of therapeutic nihilism in the treatment of advanced renal cell carcinoma, remarkable therapeutic strides have been made over the last few years. Early forays into molecularly targeted therapy for this difficult-to-treat disease were based around the inhibition of gene products of the hypoxia-inducible factor (HIF) transcription factor (i.e., VEGF). Recent data suggest that inhibition of mTOR results in clinical benefit in patients with poor prognostic features, and in preclinical models this therapeutic effect involves downregulation of HIF. Intriguingly, patients with nonclear cell histology appeared to obtain clinical benefit when treated with mTOR inhibitors. This review will highlight the mTOR pathway, its relevance to both clear cell and nonclear cell renal cell carcinoma, and its place in the host of quickly expanding treatment options. KEYWORDS: hypoxia-inducible factor • mTOR • mTOR inhibitor • rapamycin • renal cell carcinoma • temsirolimus Therapeutic advances in the treatment of patients with metastatic renal cell carcinoma (RCC) have, until recently, been limited. Treat- ment with cytokines, IL-2 or IFNα, has been shown to benefit only a small subset of patients. A more complete understanding of the molecu- lar basis of RCC has led to the rapid develop- ment of multitargeted kinase inhibitors and therapeutic antibodies that block the VEGF pathway. While the clinical advances and US FDA approval of these compounds has widened treatment options, the majority of patients with metastatic RCC still invariably die within 1 to 2 years of their diagnosis. Inhibitors of the mTOR pathway have recently shown promise in this difficult-to-treat malignancy. In this review, we will give: an overview of the mTOR pathway and how it is activated; the preclinical rationale for the use of mTOR inhibitors; and recent clinical trials showing clinical benefit in patients with metastatic RCC. mTOR mTOR is a serine/threonine kinase that func- tions as a gatekeeper of cell growth, metabolism and proliferation, receiving signals from a diverse set of growth factor receptors and sensors of cell stress and intracellular nutrient levels. In the 1970s, a sample of soil from Easter Island (also known as Rapa Nui) was found to contain an antifungal metabolite produced by the bac- terium Streptomyces hygroscopicus [1]. This com- pound was later named rapamycin (sirolimus), after the place of unearthing. Soon after its dis- covery, rapamycin was noted to inhibit the proliferation of mammalian cells, as well as having potent immunosuppressive effects. These captivating characteristics resulted in further investigation into its mode of action. A genetic screen in the budding yeast, Saccha- romyces cerevisiae, attempting to identify mutants that confer resistance to the growth- inhibitory properties of rapamycin, resulted in the identification and cloning of the target of rapamycin (TOR) [2]. This study also revealed that rapamycin complexes with, and requires the intracellular cofactor, FK506-binding pro- tein (FKBP)12, to both bind to and inhibit TOR function. TOR has since been extensively studied and is remarkably evolutionarily con- served from yeast to mammals, with all eukary- otic genomes examined to date containing a TOR gene (including yeast, algae, plants, worms, flies and mammals). mTOR complexes: mTORC1 & mTORC2 mTOR exists in two distinct multiprotein com- plexes, one that is sensitive to rapamycin and the other that is not. The rapamycin-sensitive com- plex (also called mTORC1) contains mTOR as well as the G protein β-subunit-like (GβL) and