title: Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma.
abstract: 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.
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Carpenter
authors.forename: E A
authors.initials: EA
authors.lastname: Haglund
authors.forename: E M
authors.initials: EM
authors.lastname: Mace
authors.forename: D
authors.initials: D
authors.lastname: Deng
authors.forename: D
authors.initials: D
authors.lastname: Martinez
authors.forename: A C
authors.initials: AC
authors.lastname: Wood
authors.forename: A K
authors.initials: AK
authors.lastname: Chow
authors.forename: D A
authors.initials: DA
authors.lastname: Weiser
authors.forename: L T
authors.initials: LT
authors.lastname: Belcastro
authors.forename: C
authors.initials: C
authors.lastname: Winter
authors.forename: S C
authors.initials: SC
authors.lastname: Bresler
authors.forename: M
authors.initials: M
authors.lastname: Vigny
authors.forename: P
authors.initials: P
authors.lastname: Mazot
authors.forename: S
authors.initials: S
authors.lastname: Asgharzadeh
authors.forename: R C
authors.initials: RC
authors.lastname: Seeger
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: R
authors.initials: R
authors.lastname: Guo
authors.forename: J G
authors.initials: JG
authors.lastname: Christensen
authors.forename: J S
authors.initials: JS
authors.lastname: Orange
authors.forename: B R
authors.initials: BR
authors.lastname: Pawel
authors.forename: M A
authors.initials: MA
authors.lastname: Lemmon
authors.forename: Y P
authors.initials: YP
authors.lastname: Mossé
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D006801:Humans; D009154:Mutation / Q000276:immunology; D009447:Neuroblastoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases