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

Alessio Giubellino, Petra Bullova, Svenja Nölting, Hana Turkova, James F. Powers, Qingsong Liu, Sylvie Guichard, Arthur S. Tischler, Ashley B. Grossman, Karel Pacak

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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 keymTOR 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.

Original languageEnglish (US)
Pages (from-to)646-655
Number of pages10
JournalEndocrinology
Volume154
Issue number2
DOIs
StatePublished - Feb 1 2013

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