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Cancer Cell. 2014 Nov 10;26(5):682-94. doi: 10.1016/j.ccell.2014.09.019. Epub 2014 Nov 10.

ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma.

Author information

1
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.
2
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.
3
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.
4
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.
5
Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
6
Nucleic Acid Core Facility, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
7
Department of Biostatistics, Children's Oncology Group Statistics and Data Center, University of Florida, Gainesville, FL 32611, USA.
8
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.
9
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.
10
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.

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.

PMID:
25517749
PMCID:
PMC4269829
DOI:
10.1016/j.ccell.2014.09.019
[Indexed for MEDLINE]
Free PMC Article

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