TY - JOUR
T1 - PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer
AU - Milella, Michele
AU - Falcone, Italia
AU - Conciatori, Fabiana
AU - Matteoni, Silvia
AU - Sacconi, Andrea
AU - De Luca, Teresa
AU - Bazzichetto, Chiara
AU - Corbo, Vincenzo
AU - Simbolo, Michele
AU - Sperduti, Isabella
AU - Benfante, Antonina
AU - Del Curatolo, Anais
AU - Cesta Incani, Ursula
AU - Malusa, Federico
AU - Eramo, Adriana
AU - Sette, Giovanni
AU - Scarpa, Aldo
AU - Konopleva, Marina
AU - Andreeff, Michael
AU - McCubrey, James Andrew
AU - Blandino, Giovanni
AU - Todaro, Matilde
AU - Stassi, Giorgio
AU - De Maria Marchiano, Ruggero
AU - Cognetti, Francesco
AU - Del Bufalo, Donatella
AU - Ciuffreda, Ludovica
PY - 2017
Y1 - 2017
N2 - 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 confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified 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 benefit from combined therapeutic strategies.
AB - 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 confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified 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 benefit from combined therapeutic strategies.
KW - Multidisciplinary
KW - Multidisciplinary
UR - https://publicatt.unicatt.it/handle/10807/111922
UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85013420772&origin=inward
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85013420772&origin=inward
U2 - 10.1038/srep43013
DO - 10.1038/srep43013
M3 - Article
SN - 2045-2322
VL - 7
SP - N/A-N/A
JO - Scientific Reports
JF - Scientific Reports
IS - N/A
ER -
