title: Mechanisms of mTOR inhibitor resistance in cancer therapy.
abstract: Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that regulates cell cycle progression, protein translation, metabolism, and cellular proliferation. The mTOR pathway promotes cell proliferation under energy or nutrient-rich conditions by increasing ribosomal biogenesis and protein synthesis. Since enhanced activity of the mTOR pathway is frequently observed in malignant cells, inhibition of this kinase has become an attractive strategy to treat cancer. Rapamycin and its analogs temsirolimus, everolimus, and ridaforolimus referred to as "rapalogs" have demonstrated promising efficacy against renal cell carcinoma and are under investigation for the treatment of other malignancies. However, the emergence of drug resistance may ultimately limit the utility of rapalog therapy. Here we summarize the known mechanisms of resistance to mTOR-inhibitor therapy and describe potential strategies to overcome these for the current agents that target this pathway.
authors.affiliation: Department of Medicine and Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center, 14960 Omicron Drive, San Antonio, TX 78245, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Carew
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kelly
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000903:Antibiotics, Antineoplastic; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus