Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status con rmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic pro le modi cation(s) in response to combined MEK/mTOR inhibition in PTEN- loss contexts and identi ed JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of bene t from combined therapeutic strategies.
Milella, M., Falcone, I., Conciatori, F., Matteoni, S., Sacconi, A., De Luca, T., Bazzichetto, C., Corbo, V., Simbolo, M., Sperduti, I., Benfante, A., Del Curatolo, A., Cesta Incani, U., Malusa, F., Eramo, A., Sette, G., Scarpa, A., Konopleva, M., Andreeff, M., Mccubrey, J., Blandino, G., Todaro, M., Stassi, G., De Maria Marchiano, R., Cognetti, F., Del Bufalo, D., Ciuffreda, L., PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer, <<SCIENTIFIC REPORTS>>, 2017; (n/A): N/A-N/A. [doi:10.1038/srep43013] [http://hdl.handle.net/10807/111259]
PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer
Sette, Giovanni;De Maria Marchiano, Ruggero;
2017
Abstract
Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status con rmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic pro le modi cation(s) in response to combined MEK/mTOR inhibition in PTEN- loss contexts and identi ed JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of bene t from combined therapeutic strategies.
| File | Dimensione | Formato | |
|---|---|---|---|
|
PTEN status is a crucial.pdf
accesso aperto
Tipologia file ?:
Versione Editoriale (PDF)
Licenza:
Creative commons
Dimensione
2.28 MB
Formato
Adobe PDF
|
2.28 MB | Adobe PDF | Visualizza/Apri |
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
