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Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma

Oncogene volume 31, pages 4859–4867 (2012)Cite this article

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A Corrigendum to this article was published on 15 November 2012

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.

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Acknowledgements

We thank Pfizer for their gift of crizotinib, and Dr Marc Vigny for his gift of the ALK monoclonal antibodies 30, 49, 46 and 14. This work was supported in part by NIH Grants R01-CA140198 (YPM), 2R01 CA60104-16 (RCS), 2R01 CA60104-16S1 (RCS), the Children's Oncology Group, the Carly Hillman Fund (YPM), NIH Training Grant in Structural Biology T32-GM008275 (SCB), a fellowship grant from the St Baldrick's Foundation (ACW) and the US Army Peer-Reviewed Medical Research Program (W81XWH-10-1-0212/3 to MAL/YPM).

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Authors and Affiliations

  1. Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, USA, PA

    E L Carpenter, E A Haglund, D Deng, D Martinez, A C Wood, A K Chow, D A Weiser, L T Belcastro, C Winter, B R Pawel & Y P Mossé

  2. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    J S Orange & Y P Mossé

  3. Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA

    E M Mace & M A Lemmon

  4. Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    S C Bresler

  5. Division of Hematology and Oncology, Children's Hospital of Los Angeles, Saban Research Institute, University of Southern California, Los Angeles, CA, USA

    S Asgharzadeh & R C Seeger

  6. Department of Pediatrics, Biostatistics and Data Management Core, Children's Hospital of Philadelphia, Philadelphia, PA, USA

    H Zhao & R Guo

  7. Department of Cancer Biology, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, CA, USA

    J G Christensen

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  1. E L Carpenter
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Correspondence to Y P Mossé.

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Carpenter, E., Haglund, E., Mace, E. et al. Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. Oncogene 31, 4859–4867 (2012). https://doi.org/10.1038/onc.2011.647

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