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.
| Original language | English |
|---|---|
| Pages (from-to) | 40073-40084 |
| Number of pages | 12 |
| Journal | Oncotarget |
| Volume | 7 |
| Issue number | 26 |
| Publication status | Published - 2016 |
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Keywords
- Everolimus
- Everolimus resistance
- FKBP12
- Met
ASJC Scopus subject areas
- Oncology
Cite this
Everolimus induces Met inactivation by disrupting the FKBP12/Met complex. / Raimondo, Lucia; D'Amato, Valentina; Servetto, Alberto; Rosa, Roberta; Marciano, Roberta; Formisano, Luigi; di Mauro, Concetta; Orsini, Roberta Clara; Cascetta, Priscilla; Ciciola, Paola; de Maio, Ana Paula; di Renzo, Maria Flavia; Cosconati, Sandro; Bruno, Agostino; Randazzo, Antonio; Napolitano, Filomena; Montuori, Nunzia; Veneziani, Bianca Maria; de Placido, Sabino; Bianco, Roberto.
In: Oncotarget, Vol. 7, No. 26, 2016, p. 40073-40084.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Everolimus induces Met inactivation by disrupting the FKBP12/Met complex
AU - Raimondo, Lucia
AU - D'Amato, Valentina
AU - Servetto, Alberto
AU - Rosa, Roberta
AU - Marciano, Roberta
AU - Formisano, Luigi
AU - di Mauro, Concetta
AU - Orsini, Roberta Clara
AU - Cascetta, Priscilla
AU - Ciciola, Paola
AU - de Maio, Ana Paula
AU - di Renzo, Maria Flavia
AU - Cosconati, Sandro
AU - Bruno, Agostino
AU - Randazzo, Antonio
AU - Napolitano, Filomena
AU - Montuori, Nunzia
AU - Veneziani, Bianca Maria
AU - de Placido, Sabino
AU - Bianco, Roberto
PY - 2016
Y1 - 2016
N2 - 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.
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.
KW - Everolimus
KW - Everolimus resistance
KW - FKBP12
KW - Met
UR - http://www.scopus.com/inward/record.url?scp=84982893605&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84982893605&partnerID=8YFLogxK
M3 - Article
VL - 7
SP - 40073
EP - 40084
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 26
ER -