title: Synergistic anti-tumor effects of RAD001 with MEK inhibitors in neuroendocrine tumors: a potential mechanism of therapeutic limitation of mTOR inhibitor.
abstract: Mammalian target of rapamycin (mTOR) inhibitors have been clinically used as anticancer agents in several types of human malignancies including neuroendocrine tumor (NET) but the development of clinical resistances or their therapeutic limitations have been also reported. This clinical resistance has been proposed to be partly due to a compensatory activation of an mTOR upstream factor Akt and MEK/ERK pathway in NET cells but its details have not necessarily been reported. Therefore, in this study, we examined the effects of mTOR inhibitors on these activations and of the concomitant treatment of mTOR and MEK inhibitors in two NET cell lines, NCI-H727 and COLO320. We evaluated the effects of RAD001, mTOR inhibitor, and U0126, MEK inhibitor, on cell proliferation and migration of these cells. In addition, an alteration of the factors involved in Akt/mTOR and MEK/ERK pathways was also examined under administration of these agents. RAD001 and U0126 treatment significantly inhibited cell proliferation and their combined treatment synergistically decreased it in both cell lines. Additionally, these treatments above decreased the expression of cell cycle-related factors, suggestive of an involvement of cell cycle arrest in therapeutic effects. The combined treatment also inhibited the cell migration in NCI-H727 via the decrement of MMP2 and 9 in an additive manner. We demonstrated the potential synergistic/combined effects of inhibitors of mTOR and MEK on cell proliferation and migration. These results suggest the potential therapeutic efficacy of the combined therapy of mTOR and MEK inhibitors or a dual inhibitor for the treatment of NET patients.
authors.affiliation: Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Iida
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miki
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Ono
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Akahira
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D053379:Chromogranin A / Q000378:metabolism; D004357:Drug Synergism; D000068338:Everolimus; D015870:Gene Expression; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D018358:Neuroendocrine Tumors; D009570:Nitriles / Q000494:pharmacology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D016708:Synaptophysin; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D018797:Cell Cycle Proteins; D053379:Chromogranin A; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C569014:SYP protein, human; D016708:Synaptophysin; C113580:U 0126; D033921:Vesicular Transport Proteins; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D010751:Phosphopyruvate Hydratase; D020123:Sirolimus