PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

Michele Milella; Italia Falcone; Fabiana Conciatori; Silvia Matteoni; Andrea Sacconi; Teresa De Luca; Chiara Bazzichetto; Vincenzo Corbo; Michele Simbolo; Isabella Sperduti; Antonina Benfante; Anais Del Curatolo; Ursula Cesta Incani; Federico Malusa; Adriana Eramo; Giovanni Sette; Aldo Scarpa; Marina Konopleva; Michael Andreeff; James Andrew McCubrey; Giovanni Blandino; Matilde Todaro; Giorgio Stassi; Ruggero De Maria; Francesco Cognetti; Donatella Del Bufalo; Ludovica Ciuffreda

doi:10.1038/srep43013

PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

Michele Milella, Italia Falcone, Fabiana Conciatori, Silvia Matteoni, Andrea Sacconi, Teresa De Luca, Chiara Bazzichetto, Vincenzo Corbo, Michele Simbolo, Isabella Sperduti, Antonina Benfante, Anais Del Curatolo, Ursula Cesta Incani, Federico Malusa, Adriana Eramo, Giovanni Sette, Aldo Scarpa, Marina Konopleva, Michael Andreeff, James Andrew McCubreyGiovanni Blandino, Matilde Todaro, Giorgio Stassi, Ruggero De Maria, Francesco Cognetti, Donatella Del Bufalo, Ludovica Ciuffreda

Leukemia

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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 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.

Original language	English (US)
Article number	43013
Journal	Scientific reports
Volume	7
DOIs	https://doi.org/10.1038/srep43013
State	Published - Feb 21 2017

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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., ... Ciuffreda, L. (2017). PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer. Scientific reports, 7, Article 43013. https://doi.org/10.1038/srep43013

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, JA, Blandino, G, Todaro, M, Stassi, G, De Maria, R, Cognetti, F, Del Bufalo, D & Ciuffreda, L 2017, 'PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer', Scientific reports, vol. 7, 43013. https://doi.org/10.1038/srep43013

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title = "PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer",

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 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.",

author = "Michele Milella and Italia Falcone and Fabiana Conciatori and Silvia Matteoni and Andrea Sacconi and {De Luca}, Teresa and Chiara Bazzichetto and Vincenzo Corbo and Michele Simbolo and Isabella Sperduti and Antonina Benfante and {Del Curatolo}, Anais and {Cesta Incani}, Ursula and Federico Malusa and Adriana Eramo and Giovanni Sette and Aldo Scarpa and Marina Konopleva and Michael Andreeff and McCubrey, {James Andrew} and Giovanni Blandino and Matilde Todaro and Giorgio Stassi and {De Maria}, Ruggero and Francesco Cognetti and {Del Bufalo}, Donatella and Ludovica Ciuffreda",

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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, Ruggero

AU - Cognetti, Francesco

AU - Del Bufalo, Donatella

AU - Ciuffreda, Ludovica

PY - 2017/2/21

Y1 - 2017/2/21

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.

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PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

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