title: mTOR inhibitor for the treatment of hepatocellular carcinoma.
abstract: Mammalian target of rapamycin (mTOR) plays a central role in the regulation of cellular growth, proliferation, and survival via a cytoplasmic serine/threonine kinase. mTOR also works as a nutrition sensor to monitor cellular metabolism. mTOR is located downstream in the PI3K/Akt pathway, in which Akt and the tuberous sclerosis complex (TSC) 1/2 are involved, to form a signal transduction pathway. New anticancer agents that target mTOR in the PI3K/Akt pathway of the signal transduction pathways involved in cell proliferation control have recently been developed and are already commercially available. A phase III clinical trial of mTOR inhibitor for hepatocellular carcinoma (HCC) is now ongoing worldwide to expand indications. RAD001 is a signal-transduction inhibitor (STI) that targets mTOR (more specifically, mTORC1). mTORC1 signaling is intricately regulated by mitogens, growth factors, energy, and nutrients. mTORC1 is a regulator essential for general protein synthesis, located downstream of the PI3K/AKT/mTOR pathway, which is dysregulated in most human cancers. Inhibiting mTOR with molecules, such as RAD001, generates additive effects that accompany upstream and downstream target inhibition; alternatively, upstream receptor inhibition is compensated for by inhibiting the downstream pathway, even if some resistance develops against receptor inhibition regardless of initial or acquired resistance. In conclusion, RAD001 is a potential targeted agent for HCC and therefore final results of a phase III study are awaited.
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan. m-kudo@med.kindai.ac.jp
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kudo
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology*; D002986:Clinical Trials as Topic; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases