Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma

E. L. Carpenter, E. A. Haglund, E. M. MacE, D. Deng, D. Martinez, A. C. Wood, A. K. Chow, Daniel A. Weiser, L. T. Belcastro, C. Winter, S. C. Bresler, S. Asgharzadeh, R. C. Seeger, H. Zhao, R. Guo, J. G. Christensen, J. S. Orange, B. R. Pawel, M. A. Lemmon, Y. P. Mossé

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4859-4867
Number of pages9
JournalOncogene
Volume31
Issue number46
DOIs
StatePublished - Nov 15 2012
Externally publishedYes

Fingerprint

Neuroblastoma
Antibodies
Receptor Protein-Tyrosine Kinases
anaplastic lymphoma kinase
Therapeutics
Cell Line
Neoplasms
Sympathetic Nervous System
Growth
Protein-Tyrosine Kinases
Immunotherapy
Lung Neoplasms

Keywords

  • anaplastic lymphoma kinase
  • immunotherapy
  • Neuroblastoma
  • receptor tyrosine kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Carpenter, E. L., Haglund, E. A., MacE, E. M., Deng, D., Martinez, D., Wood, A. C., ... Mossé, Y. P. (2012). Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. Oncogene, 31(46), 4859-4867. https://doi.org/10.1038/onc.2011.647

Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. / Carpenter, E. L.; Haglund, E. A.; MacE, E. M.; Deng, D.; Martinez, D.; Wood, A. C.; Chow, A. K.; Weiser, Daniel A.; Belcastro, L. T.; Winter, C.; Bresler, S. C.; Asgharzadeh, S.; Seeger, R. C.; Zhao, H.; Guo, R.; Christensen, J. G.; Orange, J. S.; Pawel, B. R.; Lemmon, M. A.; Mossé, Y. P.

In: Oncogene, Vol. 31, No. 46, 15.11.2012, p. 4859-4867.

Research output: Contribution to journalArticle

Carpenter, EL, Haglund, EA, MacE, EM, Deng, D, Martinez, D, Wood, AC, Chow, AK, Weiser, DA, Belcastro, LT, Winter, C, Bresler, SC, Asgharzadeh, S, Seeger, RC, Zhao, H, Guo, R, Christensen, JG, Orange, JS, Pawel, BR, Lemmon, MA & Mossé, YP 2012, 'Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma', Oncogene, vol. 31, no. 46, pp. 4859-4867. https://doi.org/10.1038/onc.2011.647
Carpenter EL, Haglund EA, MacE EM, Deng D, Martinez D, Wood AC et al. Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. Oncogene. 2012 Nov 15;31(46):4859-4867. https://doi.org/10.1038/onc.2011.647
Carpenter, E. L. ; Haglund, E. A. ; MacE, E. M. ; Deng, D. ; Martinez, D. ; Wood, A. C. ; Chow, A. K. ; Weiser, Daniel A. ; Belcastro, L. T. ; Winter, C. ; Bresler, S. C. ; Asgharzadeh, S. ; Seeger, R. C. ; Zhao, H. ; Guo, R. ; Christensen, J. G. ; Orange, J. S. ; Pawel, B. R. ; Lemmon, M. A. ; Mossé, Y. P. / Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. In: Oncogene. 2012 ; Vol. 31, No. 46. pp. 4859-4867.
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