title: Combined inhibition of mTORC1 and mTORC2 signaling pathways is a promising therapeutic option in inhibiting pheochromocytoma tumor growth: in vitro and in vivo studies in female athymic nude mice.
abstract: Several lines of evidence, including the recent discovery of novel susceptibility genes, point out an important role for the mammalian target of rapamycin (mTOR) signaling pathway in the development of pheochromocytoma. Analyzing a set of pheochromocytomas from patients with different genetic backgrounds, we observed and confirmed a significant overexpression of key mTOR complex (mTORC) signaling mediators. Using selective ATP-competitive inhibitors targeting both mTORC1 and mTORC2, we significantly arrested the in vitro cell proliferation and blocked migration of pheochromocytoma cells as a result of the pharmacological suppression of the Akt/mTOR signaling pathway. Moreover, AZD8055, a selective ATP-competitive dual mTORC1/2 small molecular inhibitor, significantly reduced the tumor burden in a model of metastatic pheochromocytoma using female athymic nude mice. This study suggests that targeting both mTORC1 and mTORC2 is a potentially rewarding strategy and supports the application of selective inhibitors in combinatorial drug regimens for metastatic pheochromocytoma.
authors: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Alessio
authors: A
authors: Giubellino
authors: Petra
authors: P
authors: Bullova
authors: Svenja
authors: S
authors: Nölting
authors: Hana
authors: H
authors: Turkova
authors: James F
authors: JF
authors: Powers
authors: Qingsong
authors: Q
authors: Liu
authors: Sylvie
authors: S
authors: Guichard
authors: Arthur S
authors: AS
authors: Tischler
authors: Ashley B
authors: AB
authors: Grossman
authors: Karel
authors: K
authors: Pacak
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D009287:Naphthyridines / Q000494:pharmacology; D010673:Pheochromocytoma / Q000188:drug therapy / Q000556:secondary; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D009025:Morpholines; D009287:Naphthyridines; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases