title: ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma.
abstract: Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples--at three hot spots and 13 minor sites--and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from nononcogenic mutations and allowed robust computational prediction of their effects. The mutated variants also showed differential in vitro crizotinib sensitivities. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma and will allow tailoring of ALK-targeted therapy to specific mutations.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Medical Scientist Training Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Bresler
authors.affiliation: Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Weiser
authors.affiliation: Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Huwe
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Jin H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Kateryna
authors.initials: K
authors.lastname: Krytska
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Ryles
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Marci
authors.initials: M
authors.lastname: Laudenslager
authors.affiliation: Nucleic Acid Core Facility, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Rappaport
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Wood
authors.affiliation: Department of Biostatistics, Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: McGrady
authors.affiliation: Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
authors.affiliation: Department of Biostatistics, Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, FL 32611, USA; Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber/Harvard Cancer Center, Boston, MA 02115, USA.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: London
authors.affiliation: Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Radhakrishnan
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: mlemmon@mail.med.upenn.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lemmon
authors.affiliation: Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: mosse@email.chop.edu.
authors.forename: Yaël P
authors.initials: YP
authors.lastname: Mossé
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000077547:Crizotinib; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006860:Hydrogen Bonding; D007223:Infant; D053208:Kaplan-Meier Estimate; D007700:Kinetics; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D009857:Oncogenes; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases