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

M Milella; I Falcone; F Conciatori; S Matteoni; A Sacconi; Luca T De; C Bazzichetto; V Corbo; M Simbolo; I Sperduti; A Benfante; Curatolo A Del; Incani U Cesta; F Malusa; A Eramo; G Sette; A Scarpa; M Konopleva; M Andreeff; McCubrey JA; G Blandino; M Todaro; G Stassi; Ruggero De Maria Marchiano; F Cognetti; Bufalo D Del; L. Ciuffreda

doi:10.1038/srep43013

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

M Milella^*, I Falcone, F Conciatori, S Matteoni, A Sacconi, Luca T De, C Bazzichetto, V Corbo, M Simbolo, I Sperduti, A Benfante, Curatolo A Del, Incani U Cesta, F Malusa, A Eramo, G Sette, A Scarpa, M Konopleva, M Andreeff, McCubrey JAG Blandino, M Todaro, G Stassi, Ruggero De Maria Marchiano, F Cognetti, Bufalo D Del, L. Ciuffreda

^*Autore corrispondente per questo lavoro

IRCCS Istituti fisioterapici ospitalieri - Istituto Regina Elena

Risultato della ricerca: Contributo in rivista › Articolo › peer review

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 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.

Lingua originale	Inglese
pagine (da-a)	N/A-N/A
Numero di pagine	15
Rivista	Scientific Reports
Numero di pubblicazione	n/A
DOI	https://doi.org/10.1038/srep43013
Stato di pubblicazione	Pubblicato - 2017

All Science Journal Classification (ASJC) codes

Multidisciplinare

Keywords

PTEN
mTOR

OSS delle Nazioni Unite

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10.1038/srep43013

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Milella, M., Falcone, I., Conciatori, F., Matteoni, S., Sacconi, A., De, L. T., Bazzichetto, C., Corbo, V., Simbolo, M., Sperduti, I., Benfante, A., Del, C. A., Cesta, I. 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, (n/A), N/A-N/A. 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 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.",

keywords = "PTEN, mTOR, PTEN, mTOR",

author = "M Milella and I Falcone and F Conciatori and S Matteoni and A Sacconi and De, {Luca T} and C Bazzichetto and V Corbo and M Simbolo and I Sperduti and A Benfante and Del, {Curatolo A} and Cesta, {Incani U} and F Malusa and A Eramo and G Sette and A Scarpa and M Konopleva and M Andreeff and McCubrey JA and G Blandino and M Todaro and G Stassi and {De Maria Marchiano}, Ruggero and F Cognetti and Del, {Bufalo D} and L. Ciuffreda",

year = "2017",

doi = "10.1038/srep43013",

language = "English",

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

journal = "Scientific Reports",

issn = "2045-2322",

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Milella, M, Falcone, I, Conciatori, F, Matteoni, S, Sacconi, A, De, LT, Bazzichetto, C, Corbo, V, Simbolo, M, Sperduti, I, Benfante, A, Del, CA, Cesta, IU, Malusa, F, Eramo, A, Sette, G, Scarpa, A, Konopleva, M, Andreeff, M, JA, M, Blandino, G, Todaro, M, Stassi, G, De Maria Marchiano, R, Cognetti, F, Del, BD & Ciuffreda, L 2017, 'PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer', Scientific Reports, n. n/A, 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 - Milella, M

AU - Falcone, I

AU - Conciatori, F

AU - Matteoni, S

AU - Sacconi, A

AU - De, Luca T

AU - Bazzichetto, C

AU - Corbo, V

AU - Simbolo, M

AU - Sperduti, I

AU - Benfante, A

AU - Del, Curatolo A

AU - Cesta, Incani U

AU - Malusa, F

AU - Eramo, A

AU - Sette, G

AU - Scarpa, A

AU - Konopleva, M

AU - Andreeff, M

AU - JA, McCubrey

AU - Blandino, G

AU - Todaro, M

AU - Stassi, G

AU - De Maria Marchiano, Ruggero

AU - Cognetti, F

AU - Del, Bufalo D

AU - Ciuffreda, L.

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 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.

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 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.

KW - PTEN

KW - mTOR

KW - PTEN

KW - mTOR

UR - https://publicatt.unicatt.it/handle/10807/111259

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U2 - 10.1038/srep43013

DO - 10.1038/srep43013

M3 - Article

SN - 2045-2322

SP - N/A-N/A

JO - Scientific Reports

JF - Scientific Reports

IS - n/A

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Keywords

OSS delle Nazioni Unite

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