PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer
Milella, Michele; Falcone, Italia; Conciatori, Fabiana; Matteoni, Silvia; Sacconi, Andrea; De Luca, Teresa; Bazzichetto, Chiara; Corbo, Vincenzo; Simbolo, Michele; Sperduti, Isabella; Benfante, Antonina; Del Curatolo, Anais; Incani, Ursula Cesta; Malusa, Federico; Eramo, Adriana; Sette, Giovanni; Scarpa, Aldo; Konopleva, Marina; Andreeff, Michael; McCubrey, James Andrew; Blandino, Giovanni; Todaro, Matilde; Stassi, Giorgio; De Maria, Ruggero; Cognetti, Francesco; Del Bufalo, Donatella; Ciuffreda, Ludovica
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.
Milella, Michele, & Falcone, Italia, & Conciatori, Fabiana, & Matteoni, Silvia, & Sacconi, Andrea, & De Luca, Teresa, & Bazzichetto, Chiara, & Corbo, Vincenzo, & Simbolo, Michele, & Sperduti, Isabella, & Benfante, Antonina, & Del Curatolo, Anais, & Incani, Ursula Cesta, & Malusa, Federico, & Eramo, Adriana, & Sette, Giovanni, & Scarpa, Aldo, & Konopleva, Marina, & Andreeff, Michael, & McCubrey, James Andrew, & Blandino, Giovanni, & Todaro, Matilde, & Stassi, Giorgio, & De Maria, Ruggero, & Cognetti, Francesco, & Del Bufalo, Donatella, & Ciuffreda, Ludovica. (February 2017). PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer. Scientific Reports, (7:1), p.. Retrieved from http://hdl.handle.net/10342/8276
Milella, Michele, and Falcone, Italia, and Conciatori, Fabiana, and Matteoni, Silvia, and Sacconi, Andrea, and De Luca, Teresa, and Bazzichetto, Chiara, and Corbo, Vincenzo, and Simbolo, Michele, and Sperduti, Isabella, and Benfante, Antonina, and Del Curatolo, Anais, and Incani, Ursula Cesta, and Malusa, Federico, and Eramo, Adriana, and Sette, Giovanni, and Scarpa, Aldo, and Konopleva, Marina, and Andreeff, Michael, and McCubrey, James Andrew, and Blandino, Giovanni, and Todaro, Matilde, and Stassi, Giorgio, and De Maria, Ruggero, and Cognetti, Francesco, and Del Bufalo, Donatella, and Ciuffreda, Ludovica. "PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer". Scientific Reports. 7:1. (.), February 2017. October 30, 2020. http://hdl.handle.net/10342/8276.
Milella, Michele and Falcone, Italia and Conciatori, Fabiana and Matteoni, Silvia and Sacconi, Andrea and De Luca, Teresa and Bazzichetto, Chiara and Corbo, Vincenzo and Simbolo, Michele and Sperduti, Isabella and Benfante, Antonina and Del Curatolo, Anais and Incani, Ursula Cesta and Malusa, Federico and Eramo, Adriana and Sette, Giovanni and Scarpa, Aldo and Konopleva, Marina and Andreeff, Michael and McCubrey, James Andrew and Blandino, Giovanni and Todaro, Matilde and Stassi, Giorgio and De Maria, Ruggero and Cognetti, Francesco and Del Bufalo, Donatella and Ciuffreda, Ludovica, "PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer," Scientific Reports 7, no. 1 (February 2017), http://hdl.handle.net/10342/8276 (accessed October 30, 2020).
Milella, Michele, Falcone, Italia, Conciatori, Fabiana, Matteoni, Silvia, Sacconi, Andrea, De Luca, Teresa, Bazzichetto, Chiara, Corbo, Vincenzo, Simbolo, Michele, Sperduti, Isabella, Benfante, Antonina, Del Curatolo, Anais, Incani, Ursula Cesta, Malusa, Federico, Eramo, Adriana, Sette, Giovanni, Scarpa, Aldo, Konopleva, Marina, Andreeff, Michael, McCubrey, James Andrew, Blandino, Giovanni, Todaro, Matilde, Stassi, Giorgio, De Maria, Ruggero, Cognetti, Francesco, Del Bufalo, Donatella, Ciuffreda, Ludovica. PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer. Scientific Reports. February 2017; 7(1) . http://hdl.handle.net/10342/8276. Accessed October 30, 2020.