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.
authors.affiliation: Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.affiliation: Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Italia
authors.initials: I
authors.lastname: Falcone
authors.affiliation: Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Conciatori
authors.affiliation: Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Matteoni
authors.affiliation: Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sacconi
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: De Luca
authors.affiliation: Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Bazzichetto
authors.affiliation: ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Corbo
authors.affiliation: ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Simbolo
authors.affiliation: Biostatistics, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: DiBiMIS, University of Palermo, Palermo, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Benfante
authors.affiliation: Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Anais
authors.initials: A
authors.lastname: Del Curatolo
authors.affiliation: Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Ursula
authors.initials: U
authors.lastname: Cesta Incani
authors.affiliation: Data Analysis Unit, Siena Biotech S.p.A. Siena, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Malusa
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Eramo
authors.affiliation: DiBiMIS, University of Palermo, Palermo, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sette
authors.affiliation: ARC-Net Research Centre and Department of Pathology, University of Verona, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of  Texas MD Anderson Cancer Center, Houston (TX), USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of  Texas MD Anderson Cancer Center, Houston (TX), USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: Department of Microbiology &Immunology, Brody School of Medicine, East Carolina University, Greenville (NC), USA.
authors.forename: James Andrew
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Translational Oncogenomic Unit, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Blandino
authors.affiliation: DiBiMIS, University of Palermo, Palermo, Italy.
authors.forename: Matilde
authors.initials: M
authors.lastname: Todaro
authors.affiliation: DiBiMIS, University of Palermo, Palermo, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Stassi
authors.affiliation: Scientific Direction, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
authors.affiliation: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Del Bufalo
authors.affiliation: Medical Oncology 1, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Ciuffreda
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004357:Drug Synergism; D000068338:Everolimus / Q000494:pharmacology; D005260:Female; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000068338:Everolimus; D053613:Janus Kinase 1; D020930:MAP Kinase Kinase Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D011744:Pyrimidinones; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D058570:TOR Serine-Threonine Kinases; C494086:STAT3 protein, human; C560077:trametinib; C546842:MTOR protein, human; C507904:JAK1 protein, human; C494929:PTEN protein, human