Some forms of neuroblastoma, an often-deadly childhood cancer of the peripheral nervous system, may be treatable with the protein-kinase inhibitor crizotinib, a drug already approved for treatment of certain cancers of adults.

About 10% of neuroblastomas are characterized by a mutation in the gene that encodes the enzyme anaplastic lymphoma kinase (ALK). The most frequent ALK mutations in neuroblastoma cause amino acid substitutions (F1174L and R1275Q) in the intracellular tyrosine kinase domain of the intact ALK receptor.

Investigators at the Children’s Hospital of Philadelphia (PA, USA) and the University of Pennsylvania (Philadelphia, USA) assessed the ability of crizotinib to inhibit proliferation of neuroblastoma cell lines and xenografts expressing mutated or wild type ALK.

They reported in the November 9, 2011, issue of the journal Science Translational Medicine that crizotinib inhibited proliferation of cell lines expressing either R1275Q-mutated ALK or amplified wild-type ALK. In contrast, cell lines harboring F1174L-mutated ALK were relatively resistant to crizotinib.

The investigators found that at the molecular level the reduced susceptibility of F1174L-mutated ALK to crizotinib inhibition resulted from an increased adenosine triphosphate (ATP)–binding affinity that prevented the drug from displacing ATP and binding to the ALK target molecule. They suggested that these results justify increasing the dosage of crizotinib in patients with the more drug-resistant mutation.

“This scientific study allows us to move ahead in improving drug treatments for children with a particular form of neuroblastoma,” said senior author Dr. Yaël P. Mossé, professor of pediatric oncology at the Children’s Hospital of Philadelphia. “This study shows how important it is to integrate basic science into the design of clinical trials, and how useful it can be.”

 

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