title: Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma.
abstract: Activating mutations in the anaplastic lymphoma kinase (ALK) gene were recently discovered in neuroblastoma, a cancer of the developing autonomic nervous system that is the most commonly diagnosed malignancy in the first year of life. The most frequent ALK mutations in neuroblastoma cause amino acid substitutions (F1174L and R1275Q) in the intracellular tyrosine kinase domain of the intact ALK receptor. Identification of ALK as an oncogenic driver in neuroblastoma suggests that crizotinib (PF-02341066), a dual-specific inhibitor of the ALK and Met tyrosine kinases, will be useful in treating this malignancy. Here, we assessed the ability of crizotinib to inhibit proliferation of neuroblastoma cell lines and xenografts expressing mutated or wild-type ALK. Crizotinib inhibited proliferation of cell lines expressing either R1275Q-mutated ALK or amplified wild-type ALK. In contrast, cell lines harboring F1174L-mutated ALK were relatively resistant to crizotinib. Biochemical analyses revealed that this reduced susceptibility of F1174L-mutated ALK to crizotinib inhibition resulted from an increased adenosine triphosphate-binding affinity (as also seen in acquired resistance to epidermal growth factor receptor inhibitors). Thus, this effect should be surmountable with higher doses of crizotinib and/or with higher-affinity inhibitors.
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6059, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Bresler
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Wood
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Haglund
authors.forename: Joshua
authors.initials: J
authors.lastname: Courtright
authors.forename: Lili T
authors.initials: LT
authors.lastname: Belcastro
authors.forename: Jefferson S
authors.initials: JS
authors.lastname: Plegaria
authors.forename: Kristina
authors.initials: K
authors.lastname: Cole
authors.forename: Yana
authors.initials: Y
authors.lastname: Toporovskaya
authors.forename: Huaqing
authors.initials: H
authors.lastname: Zhao
authors.forename: Erica L
authors.initials: EL
authors.lastname: Carpenter
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lemmon
authors.forename: Yaël P
authors.initials: YP
authors.lastname: Mossé
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D050505:Mutant Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D000255:Adenosine Triphosphate; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
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