Everolimus induces Met inactivation by disrupting the FKBP12/Met complex
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Lucia Raimondo1, Valentina D’Amato1, Alberto Servetto1, Roberta Rosa1, Roberta Marciano1, Luigi Formisano1, Concetta Di Mauro1, Roberta Clara Orsini1, Priscilla Cascetta1, Paola Ciciola1, Ana Paula De Maio1, Maria Flavia Di Renzo2, Sandro Cosconati3, Agostino Bruno4, Antonio Randazzo4, Filomena Napolitano5, Nunzia Montuori5, Bianca Maria Veneziani6, Sabino De Placido1, Roberto Bianco1
1Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy
2Department of Oncology, University of Turin, Candiolo Cancer Institute - FPO IRCCS, Turin, Italy
3DiSTABiF, Second University of Naples, Caserta, Italy
4Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
5Department of Translational Medical Sciences, University of Naples “Federico II”, Naples, Italy
6Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy
Roberto Bianco, email: [email protected]
Keywords: everolimus, Met, FKBP12, everolimus resistance
Received: March 21, 2016 Accepted: April 26, 2016 Published: May 19, 2016
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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