Mammalian target of rapamycin inhibitors in renal cell carcinoma: current status and future applications.
Significant achievements in the basic sciences have led to a greater knowledge of the underlying signaling pathways in renal cell cancer (RCC), including the mammalian target of rapamycin (mTOR) pathway (phosphoinositide 3-kinase/Akt pathway). The mTOR pathway has a central role in the regulation of cell growth and increasing evidence suggests its dysregulation in cancer. Receiving input from multiple signals, including growth factors, hormones, nutrients, and other stimulants or mitogens, the pathway stimulates protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase. The mTOR pathway also contributes to many other critical cellular functions, including protein degradation and angiogenesis. Hence, use of inhibitors of the pathway represents a new strategy for the targeted treatment of RCC, and mTOR inhibitors have already shown promising clinical efficacy and low toxicity profiles in unselected patients with metastatic RCC. As with other new, targeted cancer agents, the future use of mTOR inhibitors will benefit from reproducible biomarkers that can be used in the clinic to identify patients most likely to respond and to document modulation of the drug target in addition to clinical response.
Pantuck
Allan J
AJ
Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1738, USA. apantuck@mednet.ucla.edu
Thomas
George
G
Belldegrun
Arie S
AS
Figlin
Robert A
RA
D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases
D004791:Enzyme Inhibitors; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases