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

Ruggero De Maria Marchiano; Giovanni Sette; 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; Aldo Scarpa; Marina Konopleva; Michael Andreeff; James Andrew Mccubrey; Giovanni Blandino; Matilde Todaro; Giorgio Stassi; 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

Ruggero De Maria Marchiano, Giovanni Sette, 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, Aldo Scarpa, Marina Konopleva, Michael AndreeffJames Andrew Mccubrey, Giovanni Blandino, Matilde Todaro, Giorgio Stassi, Francesco Cognetti, Donatella Del Bufalo, Ludovica Ciuffreda

Risultato della ricerca: Contributo in rivista › Articolo in rivista

36 Citazioni (Scopus)

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.

Lingua originale	English
pagine (da-a)	N/A-N/A
Rivista	Scientific Reports
Volume	7
DOI	https://doi.org/10.1038/srep43013
Stato di pubblicazione	Pubblicato - 2017

Keywords

Multidisciplinary

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10.1038/srep43013

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De Maria Marchiano, R., Sette, G., 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., Scarpa, A., Konopleva, 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, N/A-N/A. https://doi.org/10.1038/srep43013

@article{2539fe2670954e4788d0d82879419205,

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.",

keywords = "Multidisciplinary, Multidisciplinary",

author = "{De Maria Marchiano}, Ruggero and Giovanni Sette and 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 Aldo Scarpa and Marina Konopleva and Michael Andreeff and Mccubrey, {James Andrew} and Giovanni Blandino and Matilde Todaro and Giorgio Stassi and Francesco Cognetti and {Del Bufalo}, Donatella and Ludovica Ciuffreda",

year = "2017",

doi = "10.1038/srep43013",

language = "English",

volume = "7",

pages = "N/A--N/A",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "London : Nature Publishing Group",

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De Maria Marchiano, R, Sette, G, 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, Scarpa, A, Konopleva, M, Andreeff, M, Mccubrey, JA, Blandino, G, Todaro, M, Stassi, G, 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, pagg. N/A-N/A. https://doi.org/10.1038/srep43013

TY - JOUR

T1 - PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

AU - De Maria Marchiano, Ruggero

AU - Sette, Giovanni

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 - Scarpa, Aldo

AU - Konopleva, Marina

AU - Andreeff, Michael

AU - Mccubrey, James Andrew

AU - Blandino, Giovanni

AU - Todaro, Matilde

AU - Stassi, Giorgio

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

UR - http://hdl.handle.net/10807/111922

UR - http://www.nature.com/srep/index.html

U2 - 10.1038/srep43013

DO - 10.1038/srep43013

M3 - Article

VL - 7

SP - N/A-N/A

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

ER -

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

Abstract

Keywords

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