Research ArticleNeuroblastoma

Differential Inhibitor Sensitivity of Anaplastic Lymphoma Kinase Variants Found in Neuroblastoma

Science Translational Medicine  09 Nov 2011:
Vol. 3, Issue 108, pp. 108ra114
DOI: 10.1126/scitranslmed.3002950

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A Boost for Neuroblastoma Therapy

Neuroblastoma, a malignancy of the autonomic nervous system, is the most common cancer in children under 1 year of age. Nearly 10% of spontaneous neuroblastoma patients house mutations in the gene that encodes anaplastic lymphoma kinase (ALK). The U.S. Food and Drug Administration recently approved crizotinib—a small-molecule inhibitor of ALK’s tyrosine kinase activity and thus its cell signaling function—for the treatment of non–small cell lung carcinomas, and the drug is in early clinical trials for neuroblastoma. However, tumors with certain ALK mutations do not appear to respond to crizotinib. Bresler et al. now dissect the molecular mechanisms behind the differential crizotinib sensitivities of individual ALK mutations.

Crizotinib inhibits kinase activity by competing for binding with the enzyme’s adenosine triphosphate (ATP) substrate. The authors used human neuroblastoma cell lines and xenografts in mice to show that cancers with the two most common ALK mutations, F1174L and R1275Q, are unresponsive to and effectively inhibited by crizotinib therapy, respectively. This reduced sensitivity was caused by a heightened ATP-binding affinity in F1174L-mutated ALK. These observations suggest that either increasing the dose of crizotinib or engineering higher-affinity inhibitors should improve therapy for patients with this common ALK mutation. Although careful toxicity studies need to be performed to find the maximum tolerated dose in the pediatric population, this mechanistic study provides more than a baby step toward improving crizotinib therapy in the clinic.


  • * These authors contributed equally to this work.