Raimondo, Lucia (2017) EVEROLIMUS INDUCES MET INHIBITION BY INTEREFERING WITH FKBP12 DEPENDENT ACTIVATION”. [Tesi di dottorato]

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Item Type: Tesi di dottorato
Lingua: English
Title: EVEROLIMUS INDUCES MET INHIBITION BY INTEREFERING WITH FKBP12 DEPENDENT ACTIVATION”
Creators:
CreatorsEmail
Raimondo, Lucialucia.raimondo@unina.it
Date: 11 December 2017
Number of Pages: 34
Institution: Università degli Studi di Napoli Federico II
Department: dep13
Dottorato: phd053
Ciclo di dottorato: 30
Coordinatore del Corso di dottorato:
nomeemail
Di Minno, Giovannidiminno@unina.it
Tutor:
nomeemail
De Placido, SabinoUNSPECIFIED
Bianco, RobertoUNSPECIFIED
Date: 11 December 2017
Number of Pages: 34
Uncontrolled Keywords: Everolimus, Met, FKBP12
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/06 - Oncologia medica
Date Deposited: 21 Dec 2017 08:36
Last Modified: 19 Mar 2019 11:45
URI: http://www.fedoa.unina.it/id/eprint/12227

Abstract

Inhibition of the mechanistic target of rapamycin (mTOR) is a promising treatment strategy for several cancer types. Rapamycin derivatives such as everolimus are allosteric mTOR inhibitors acting through interaction with the intracellular immunophilin FKBP12, a prolyl isomerase with different cellular functions. Although mTOR inhibitors have significantly improved survival of different cancer patients, resistance and lack of predictive factors of response remain unsolved issues. To elucidate the mechanisms of resistance to everolimus, we evaluated Met activation in everolimus-sensitive/resistant human cancer cells, in vitro and in vivo. Biochemical and computational analyses were performed. Everolimus-resistant cells were xenografted into mice (10/group) and studied for their response to everolimus and Met inhibitors. The statistical significance of the in vitro results was evaluated by Student’s t test. Everolimus reduced Met phosphorylation in everolimus-sensitive cells. This event was mediated by the formation of a Met-FKBP12 complex, which in turn is disrupted by everolimus. Aberrant Met activation in everolimus-resistant cells and overexpression of wild-type/mutant Met caused everolimus resistance. Pharmacological inhibition and RNA silencing of Met are effective in condition of everolimus resistance (P<0.01). In mice xenografted with everolimus-resistant cells, the combination of everolimus with the Met inhibitor PHA665752 reduced tumor growth and induced a statistically significant survival advantage (combination vs control P=0.0005). FKBP12 binding is required for full Met activation and everolimus can inhibit Met. Persistent Met activation might sustain everolimus resistance. These results identify a novel everolimus mechanism of action and suggest the development of clinical strategies based on Met inhibitors in everolimus-resistant cancers.

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