title: Mutation-Independent Activation of the Anaplastic Lymphoma Kinase in Neuroblastoma.
abstract: Activating mutations of anaplastic lymphoma kinase (ALK) have been identified as important players in neuroblastoma development. Our goal was to evaluate the significance of overall ALK activation in neuroblastoma. Expression of phosphorylated ALK, ALK, and its putative ligands, pleiotrophin and midkine, was screened in 289 neuroblastomas and 56 paired normal tissues. ALK was expressed in 99% of tumors and phosphorylated in 48% of cases. Pleiotrophin and midkine were expressed in 58% and 79% of tumors, respectively. ALK activation was significantly higher in tumors than in paired normal tissues, together with ALK and midkine expression. ALK activation was largely independent of mutations and correlated with midkine expression in tumors. ALK activation in tumors was associated with favorable features, including a younger age at diagnosis, hyperdiploidy, and detection by mass screening. Antitumor activity of the ALK inhibitor TAE684 was evaluated in wild-type or mutated ALK neuroblastoma cell lines and xenografts. TAE684 was cytotoxic in vitro in all cell lines, especially those harboring an ALK mutation. TAE684 efficiently inhibited ALK phosphorylation in vivo in both F1174I and R1275Q xenografts but demonstrated antitumor activity only against the R1275Q xenograft. In conclusion, ALK activation occurs frequently during neuroblastoma oncogenesis, mainly through mutation-independent mechanisms. However, ALK activation is not associated with a poor outcome and is not always a driver of cell proliferation and/or survival in neuroblastoma.
authors.affiliation: Laboratory for Vectorology and Anticancer Therapeutics, Gustave Roussy, Paris-Sud University, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8203, Villejuif, France. Electronic address: marie.frugier-regairaz@ens-cachan.fr.
authors.forename: Marie
authors.initials: M
authors.lastname: Regairaz
authors.affiliation: Laboratory for Vectorology and Anticancer Therapeutics, Gustave Roussy, Paris-Sud University, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8203, Villejuif, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Munier
authors.affiliation: Laboratory for Vectorology and Anticancer Therapeutics, Gustave Roussy, Paris-Sud University, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8203, Villejuif, France; Sainte Justine University Hospital Center, University of Montréal, Montréal, Québec, Canada.
authors.forename: Hervé
authors.initials: H
authors.lastname: Sartelet
authors.affiliation: Department of Biostatistics and Epidemiology, Gustave Roussy, Villejuif, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Castaing
authors.affiliation: Histocytopathology Unit, Laboratory of Translational Research, Gustave Roussy, Villejuif, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Marty
authors.affiliation: Laboratory for Vectorology and Anticancer Therapeutics, Gustave Roussy, Paris-Sud University, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8203, Villejuif, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Renauleaud
authors.affiliation: Laboratory for Vectorology and Anticancer Therapeutics, Gustave Roussy, Paris-Sud University, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8203, Villejuif, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Doux
authors.affiliation: Research on Cell Growth, Tissue Repair and Regeneration (CRRET), Centre National de la Recherche Scientifique, University Paris-Est Créteil, Créteil, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Delbé
authors.affiliation: Research on Cell Growth, Tissue Repair and Regeneration (CRRET), Centre National de la Recherche Scientifique, University Paris-Est Créteil, Créteil, France.
authors.forename: José
authors.initials: J
authors.lastname: Courty
authors.affiliation: Department of Pathology, Bicêtre Hospital, Le Kremlin-Bicêtre, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Fabre
authors.affiliation: Department of Pediatrics, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Histocytopathology Unit, Laboratory of Translational Research, Gustave Roussy, Villejuif, France; Department of Pathology and Biobank, Gustave Roussy, Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Vielh
authors.affiliation: Department of Biostatistics and Epidemiology, Gustave Roussy, Villejuif, France.
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.affiliation: Department of Pediatrics, Gustave Roussy, Villejuif, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Valteau-Couanet
authors.affiliation: Laboratory for Vectorology and Anticancer Therapeutics, Gustave Roussy, Paris-Sud University, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8203, Villejuif, France. Electronic address: gilles.vassal@gustaveroussy.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Vassal
mesh_terms: D000293:Adolescent; D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases