title: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.
abstract: Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.
authors.affiliation: Program in Molecular Pharmacy and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: O'Reilly
authors.forename: Fredi
authors.initials: F
authors.lastname: Rojo
authors.forename: Qing-Bai
authors.initials: QB
authors.lastname: She
authors.forename: David
authors.initials: D
authors.lastname: Solit
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Debra
authors.initials: D
authors.lastname: Smith
authors.forename: Heidi
authors.initials: H
authors.lastname: Lane
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Dale L
authors.initials: DL
authors.lastname: Ludwig
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
mesh_terms: D045744:Cell Line, Tumor; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C526292:IRS1 protein, human; C546842:MTOR protein, human