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

Scott C Bresler; Daniel A Weiser; Peter J Huwe; Jin H Park; Kateryna Krytska; Hannah Ryles; Marci Laudenslager; Eric F Rappaport; Andrew C Wood; Patrick W McGrady; Michael D Hogarty; Wendy B London; Ravi Radhakrishnan; Mark A Lemmon; Yaël P Mossé

doi:10.1016/j.ccell.2014.09.019

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

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

Authors

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Anaplastic Lymphoma Kinase
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Crizotinib
Disease-Free Survival
Drug Resistance, Neoplasm
Humans
Hydrogen Bonding
Infant
Kaplan-Meier Estimate
Kinetics
Models, Molecular
Molecular Targeted Therapy
Mutation, Missense
Neuroblastoma / drug therapy
Neuroblastoma / genetics*
Neuroblastoma / mortality
Oncogenes
Protein Binding
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
Pyrazoles / pharmacology
Pyrazoles / therapeutic use*
Pyridines / pharmacology
Pyridines / therapeutic use*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
Receptor Protein-Tyrosine Kinases / chemistry
Receptor Protein-Tyrosine Kinases / genetics*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Crizotinib
ALK protein, human
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding