title: Establishment of novel cell lines recapitulating the genetic landscape of uveal melanoma and preclinical validation of mTOR as a therapeutic target.
abstract: Uveal melanoma (UM) is the most common primary tumor of the eye in adults. There is no standard adjuvant treatment to prevent metastasis and no effective therapy in the metastatic setting. We have established a unique panel of 7 UM cell lines from either patient's tumors or patient-derived tumor xenografts (PDXs). This panel recapitulates the molecular landscape of the disease in terms of genetic alterations and mutations. All the cell lines display GNAQ or GNA11 activating mutations, and importantly four of them display BAP1 (BRCA1 associated protein-1) deficiency, a hallmark of aggressive disease. The mTOR pathway was shown to be activated in most of the cell lines independent of AKT signaling. mTOR inhibitor Everolimus reduced the viability of UM cell lines and significantly delayed tumor growth in 4 PDXs. Our data suggest that mTOR inhibition with Everolimus, possibly in combination with other agents, may be considered as a therapeutic option for the management of uveal melanoma.
authors.affiliation: Biophenics Laboratory, Translational Research Department, Institut Curie, 26 rue d'Ulm, 75005 Paris, France. Electronic address: Nabil.Amirouchene-Angelozzi@curie.fr.
authors.forename: Nabil
authors.initials: N
authors.lastname: Amirouchene-Angelozzi
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Fariba.Nemati@curie.fr.
authors.forename: Fariba
authors.initials: F
authors.lastname: Nemati
authors.affiliation: Genomics Platform, Translational Research Department, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: David.Gentien@curie.fr.
authors.forename: David
authors.initials: D
authors.lastname: Gentien
authors.affiliation: Department of Tumor Biology, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Andre.Nicolas@curie.fr.
authors.forename: André
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: Institut Curie, INSERM U830, France. Electronic address: Amaury.Dumont@curie.fr.
authors.forename: Amaury
authors.initials: A
authors.lastname: Dumont
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Guillaume.Carita@curie.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Carita
authors.affiliation: Institut Curie, INSERM U830, France. Electronic address: Jacques.Camonis@curie.fr.
authors.forename: Jacques
authors.initials: J
authors.lastname: Camonis
authors.affiliation: Department of Ophthalmological Oncology, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Laurance.Desjardins@curie.net.
authors.forename: Laurence
authors.initials: L
authors.lastname: Desjardins
authors.affiliation: Department of Ophthalmological Oncology, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Nathalie.Cassoux@curie.net.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cassoux
authors.affiliation: Department of Medical Oncology, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Sophie.Piperno-Neumann@curie.net.
authors.forename: Sophie
authors.initials: S
authors.lastname: Piperno-Neumann
authors.affiliation: Department of Surgery, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Pascale.Mariani@curie.net.
authors.forename: Pascale
authors.initials: P
authors.lastname: Mariani
authors.affiliation: Department of Tumor Biology, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Xavier.Sastre@curie.net.
authors.forename: Xavier
authors.initials: X
authors.lastname: Sastre
authors.affiliation: Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Didier.Decaudin@curie.net.
authors.forename: Didier
authors.initials: D
authors.lastname: Decaudin
authors.affiliation: Translational Research Department, Institut Curie, 26, rue d'Ulm, 75005 Paris, France. Electronic address: Sergio.Roman-Roman@curie.fr.
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000068338:Everolimus; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000098943:Uveal Melanoma
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: BAP1; Cell lines; Everolimus; Patients-derived tumor xenografts; Uveal melanoma; mTOR