title: The mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma.
abstract: Uveal melanoma (UM) is the most frequent malignant ocular tumor in adults. While the primary tumor is efficiently treated by surgery and/or radiotherapy, about one third of UM patients develop metastases, for which no effective treatment is currently available. The PKC, MAPK and PI3K/AKT/mTOR signaling cascades have been shown to be associated with tumor growth. However, none of the compounds against those pathways results in tumor regression when used as single agents. To identify more effective therapeutic strategies for UM patients, we performed a combination screen using seven targeted agents inhibiting PKC, MEK, AKT, PI3K and mTOR in a panel of ten UM cell lines, representative of the UM disease. We identified a strong synergy between the mTOR inhibitor Everolimus and the PI3K inhibitor GDC0941. This combination resulted in an increase in apoptosis in several UM cell lines compared to monotherapies and enhanced the anti-tumor effect of each single agent in two patient-derived xenografts. Furthermore, we showed that the synergism between the two drugs was associated with the relief by GDC0491 of a reactivation of AKT induced by Everolimus. Altogether, our results highlight a novel and effective combination strategy, which could be beneficial for UM patients.
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University, Paris, France.|Current address: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Torino, Italy.
authors.forename: Nabil
authors.initials: N
authors.lastname: Amirouchene-Angelozzi
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Frisch-Dit-Leitz
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Carita
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Dahmani
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Raymondie
authors.affiliation: Unité Mixte de Recherche 3347, Institut Curie, PSL Research University, Orsay, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Liot
authors.affiliation: Genomics Platform, Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Gentien
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Fariba
authors.initials: F
authors.lastname: Némati
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, PSL Research University, Paris, France.|Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Schoumacher
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D000068338:Everolimus / Q000008:administration & dosage; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage; D008545:Melanoma; D051379:Mice; D016513:Mice, SCID; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D013449:Sulfonamides / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms; D023041:Xenograft Model Antitumor Assays; D000098943:Uveal Melanoma
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D014408:Biomarkers, Tumor; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: PI3K; apoptosis; mTOR; preclinical models; uveal melanoma