The
mammalian target of rapamycin (mTOR) is a key regulator of cell growth and proliferation. The mTOR pathway integrates signals from nutrients, energy status and extracellular
growth factors to regulate many processes, including cell cycle progression, angiogenesis, ribosome biogenesis, and metabolism.
Growth factors such as
insulin-like growth factor,
epidermal growth factor and
vascular endothelial growth factor bind to and activate their corresponding
tyrosine kinase receptors (TKR) located on the cell surface, to induce signal transduction to the nucleus. TKR induces intracellular signaling cascades via the phosphorylation of the
phosphatidylinositol 3-kinase, which in turn phosphorylates Akt. Of particular interest among the Akt targets is the downstream effect on mTOR, which is responsible for
protein synthesis of molecules necessary for nutrient uptake, angiogenesis, ribosome biogenesis, cell growth, and proliferation. Growing evidence suggests that mTOR deregulation is associated with many types of human
cancer. The importance of mTOR signaling in
tumor biology is now widely accepted. Consequently, a number of agents that selectively target mTOR are being developed for
cancer treatment and currently
temsirolimus and
everolimus are approved for the treatment of advanced
renal cell cancer. However, the therapeutic benefit of
mTOR inhibitors in the clinic may vary depending on the activation state of the different components of the mTOR pathway in a given case. Therefore it seems clear that predicting sensitivity to rapamycins in different
cancers will likely require assessing multiple molecular markers related to mTOR signaling pathway, such as
phosphatase and
tensin homolog (PTEN), phospho-Akt, cytoplasmic p27, and phospho-S6
kinase.