Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma

Oncogene. 2012 Nov 15;31(46):4859-67. doi: 10.1038/onc.2011.647. Epub 2012 Jan 23.


Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase aberrantly expressed in neuroblastoma, a devastating pediatric cancer of the sympathetic nervous system. Germline and somatically acquired ALK aberrations induce increased autophosphorylation, constitutive ALK activation and increased downstream signaling. Thus, ALK is a tractable therapeutic target in neuroblastoma, likely to be susceptible to both small-molecule tyrosine kinase inhibitors and therapeutic antibodies-as has been shown for other receptor tyrosine kinases in malignancies such as breast and lung cancer. Small-molecule inhibitors of ALK are currently being studied in the clinic, but common ALK mutations in neuroblastoma appear to show de novo insensitivity, arguing that complementary therapeutic approaches must be developed. We therefore hypothesized that antibody targeting of ALK may be a relevant strategy for the majority of neuroblastoma patients likely to have ALK-positive tumors. We show here that an antagonistic ALK antibody inhibits cell growth and induces in vitro antibody-dependent cellular cytotoxicity of human neuroblastoma-derived cell lines. Cytotoxicity was induced in cell lines harboring either wild type or mutated forms of ALK. Treatment of neuroblastoma cells with the dual Met/ALK inhibitor crizotinib sensitized cells to antibody-induced growth inhibition by promoting cell surface accumulation of ALK and thus increasing the accessibility of antigen for antibody binding. These data support the concept of ALK-targeted immunotherapy as a highly promising therapeutic strategy for neuroblastomas with mutated or wild-type ALK.

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
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / pharmacology*
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology
  • Antigens, Neoplasm / metabolism
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Death / immunology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crizotinib
  • Humans
  • Mutation / immunology
  • Neuroblastoma / genetics
  • Neuroblastoma / immunology*
  • Neuroblastoma / metabolism
  • Neuroblastoma / therapy*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / immunology
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / immunology*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / immunology


  • Antibodies, Monoclonal
  • Antigens, Neoplasm
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • MET protein, human
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-met
  • Receptor Protein-Tyrosine Kinases