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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.

journal_name

Oncogene

journal_title

Oncogene

authors

Carpenter EL,Haglund EA,Mace EM,Deng D,Martinez D,Wood AC,Chow AK,Weiser DA,Belcastro LT,Winter C,Bresler SC,Vigny M,Mazot P,Asgharzadeh S,Seeger RC,Zhao H,Guo R,Christensen JG,Orange JS,Pawel BR,Lemmon MA,Mossé

doi

10.1038/onc.2011.647

subject

Has Abstract

pub_date

2012-11-15 00:00:00

pages

4859-67

issue

46

eissn

0950-9232

issn

1476-5594

pii

onc2011647

journal_volume

31

pub_type

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