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

Research output: Contribution to journalArticle

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 languageEnglish
Article number43013
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - Feb 21 2017

ASJC Scopus subject areas

  • General

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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, [43013]. https://doi.org/10.1038/srep43013