PMID- 27223077 OWN - NLM STAT- MEDLINE DCOM- 20180117 LR - 20211204 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 7 IP - 26 DP - 2016 Jun 28 TI - Everolimus induces Met inactivation by disrupting the FKBP12/Met complex. PG - 40073-40084 LID - 10.18632/oncotarget.9484 [doi] AB - 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. FAU - Raimondo, Lucia AU - Raimondo L AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - D'Amato, Valentina AU - D'Amato V AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - Servetto, Alberto AU - Servetto A AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - Rosa, Roberta AU - Rosa R AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - Marciano, Roberta AU - Marciano R AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - Formisano, Luigi AU - Formisano L AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - Di Mauro, Concetta AU - Di Mauro C AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - Orsini, Roberta Clara AU - Orsini RC AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - Cascetta, Priscilla AU - Cascetta P AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - Ciciola, Paola AU - Ciciola P AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - De Maio, Ana Paula AU - De Maio AP AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - Di Renzo, Maria Flavia AU - Di Renzo MF AD - Department of Oncology, University of Turin, Candiolo Cancer Institute - FPO IRCCS, Turin, Italy. FAU - Cosconati, Sandro AU - Cosconati S AD - DiSTABiF, Second University of Naples, Caserta, Italy. FAU - Bruno, Agostino AU - Bruno A AD - Department of Pharmacy, University of Naples "Federico II", Naples, Italy. FAU - Randazzo, Antonio AU - Randazzo A AD - Department of Pharmacy, University of Naples "Federico II", Naples, Italy. FAU - Napolitano, Filomena AU - Napolitano F AD - Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. FAU - Montuori, Nunzia AU - Montuori N AD - Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy. FAU - Veneziani, Bianca Maria AU - Veneziani BM AD - Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy. FAU - De Placido, Sabino AU - De Placido S AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. FAU - Bianco, Roberto AU - Bianco R AD - Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples, Italy. LA - eng PT - Journal Article PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.10.1 (RON protein) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Allosteric Site MH - Animals MH - Cell Line, Tumor MH - *Drug Resistance, Neoplasm MH - Everolimus/*pharmacology MH - Female MH - *Gene Expression Regulation, Neoplastic MH - HCT116 Cells MH - Humans MH - Mice MH - Mice, Nude MH - Neoplasm Transplantation MH - Phosphorylation MH - RNA Interference MH - Receptor Protein-Tyrosine Kinases/*metabolism MH - TOR Serine-Threonine Kinases/*metabolism PMC - PMC5129993 OTO - NOTNLM OT - FKBP12 OT - Met OT - everolimus OT - everolimus resistance COIS- No potential conflicts of interest were disclosed. EDAT- 2016/10/26 06:00 MHDA- 2018/01/18 06:00 PMCR- 2016/06/28 CRDT- 2016/05/26 06:00 PHST- 2016/03/21 00:00 [received] PHST- 2016/04/26 00:00 [accepted] PHST- 2016/10/26 06:00 [pubmed] PHST- 2018/01/18 06:00 [medline] PHST- 2016/05/26 06:00 [entrez] PHST- 2016/06/28 00:00 [pmc-release] AID - 9484 [pii] AID - 10.18632/oncotarget.9484 [doi] PST - ppublish SO - Oncotarget. 2016 Jun 28;7(26):40073-40084. doi: 10.18632/oncotarget.9484.