Targeting mTOR in cancer: renal cell is just a beginning

Abstract

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.

Sirolimus Use and Cancer Incidence Among US Kidney Transplant Recipients

“…Sirolimus has been shown in vivo to block mTOR kinase binding activity, which is a key step in the PI3K/Akt/mTOR pathway that regulates cell growth and proliferation (20). Overactivation of this pathway is frequently observed in malignant cells and is associated with poor prognosis after a cancer diagnosis (21)(22)(23).…”

The Plasma Membrane Sialidase NEU3 Regulates the Malignancy of Renal Carcinoma Cells by Controlling β1 Integrin Internalization and Recycling

“…In particular, the PI3K/AKT pathway is constitutively active and is responsible for cell growth and survival (29). The up-regulation of the plasma membrane sialidase NEU3 in RCC has previously been demonstrated to be indirectly involved in altering PI3K/AKT signaling through hyper-activation of the IL-6 pathway (9).…”

Evidence for PTEN-independent Akt activation and Akt-independent p27Kip1 expression in advanced bladder cancer

“…Several studies support this observation. Pantuk et al (31) and Azim et al (7) studied the mTOR pathway and its components and correlated this pathway significantly with pathological findings and survival in renal cell carcinoma. These authors also stressed the importance of individual assessment of distinct molecular markers to predict individual benefit of targeted therapy.…”

“…Deregulation of Akt signalling appears to play a key role in the pathogenesis of cancer. Understanding the effect of the individual up-and downstream molecules and presumably existing deregulation of their cascades in tumour cells may shed light on prognosis, suggesting different therapeutic options and possibly targeted therapy depending on the individual changes in the signalling network (3,7).…”