ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma

Scott C. Bresler, Daniel A. Weiser, Peter J. Huwe, Jin H. Park, Kateryna Krytska, Hannah Ryles, Marci Laudenslager, Eric F. Rappaport, Andrew C. Wood, Patrick W. McGrady, Michael D. Hogarty, Wendy B. London, Ravi Radhakrishnan, Mark A. Lemmon, Yaël P. Mossé

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Abstract

Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples-at three hot spots and 13minor sites-and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from nononcogenic mutations and allowed robust computational prediction of their effects. The mutated variants also showed differential invitro crizotinib sensitivities. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma and will allow tailoring of ALK-targeted therapy to specific mutations.

Original languageEnglish (US)
Pages (from-to)682-694
Number of pages13
JournalCancer Cell
Volume26
Issue number5
DOIs
StatePublished - Nov 10 2014

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ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Bresler, S. C., Weiser, D. A., Huwe, P. J., Park, J. H., Krytska, K., Ryles, H., Laudenslager, M., Rappaport, E. F., Wood, A. C., McGrady, P. W., Hogarty, M. D., London, W. B., Radhakrishnan, R., Lemmon, M. A., & Mossé, Y. P. (2014). ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma. Cancer Cell, 26(5), 682-694. https://doi.org/10.1016/j.ccell.2014.09.019