title: Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684.
abstract: Mutations in the kinase domain of ALK (anaplastic lymphoma kinase) have recently been shown to be important for the progression of the childhood tumour neuroblastoma. In the present study we investigate six of the putative reported constitutively active ALK mutations, in positions G1128A, I1171N, F1174L, R1192P, F1245C and R1275Q. Our analyses were performed in cell-culture-based systems with both mouse and human ALK mutant variants and subsequently in a Drosophila melanogaster model system. Our investigation addressed the transforming potential of the putative gain-of-function ALK mutations as well as their signalling potential and the ability of two ATP-competitive inhibitors, Crizotinib (PF-02341066) and NVP-TAE684, to abrogate the activity of ALK. The results of the present study indicate that all mutations tested are of an activating nature and thus are implicated in tumour initiation or progression of neuroblastoma. Importantly for neuroblastoma patients, all ALK mutations used in the present study can be blocked by the inhibitors, although some mutants exhibited higher levels of drug sensitivity than others.
authors.affiliation: Department of Molecular Biology, Building 6L, Umeå University, Umeå 901 87, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Schönherr
authors.forename: Kristina
authors.initials: K
authors.lastname: Ruuth
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Therese
authors.initials: T
authors.lastname: Eriksson
authors.forename: James
authors.initials: J
authors.lastname: Christensen
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Palmer
authors.forename: Bengt
authors.initials: B
authors.lastname: Hallberg
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D054910:Compound Eye, Arthropod / Q000002:abnormalities / Q000187:drug effects; D000077547:Crizotinib; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D016501:Neurites / Q000187:drug effects; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics*; D016716:PC12 Cells; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C516714:NVP-TAE684; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases