Neuroblastoma is a childhood extracranial solid tumour that is associated with a 
number of genetic changes. Included in these genetic alterations are mutations 
in the kinase domain of the anaplastic lymphoma kinase (ALK) receptor tyrosine 
kinase (RTK), which have been found in both somatic and familial neuroblastoma. 
In order to treat patients accordingly requires characterisation of these 
mutations in terms of their response to ALK tyrosine kinase inhibitors (TKIs). 
Here, we report the identification and characterisation of two novel 
neuroblastoma ALK mutations (A1099T and R1464STOP), which we have investigated 
together with several previously reported but uncharacterised ALK mutations 
(T1087I, D1091N, T1151M, M1166R, F1174I and A1234T). In order to understand the 
potential role of these ALK mutations in neuroblastoma progression, we have 
employed cell culture-based systems together with the model organism Drosophila 
as a readout for ligand-independent activity. Mutation of ALK at position 1174 
(F1174I) generates a gain-of-function receptor capable of activating 
intracellular targets such as ERK (extracellular signal regulated kinase) and 
STAT3 (signal transducer and activator of transcription 3) in a 
ligand-independent manner. Analysis of these previously uncharacterised ALK 
mutants and comparison with ALK(F1174) mutants suggests that ALK mutations 
observed in neuroblastoma fall into three classes. These classes are: (i) 
gain-of-function ligand-independent mutations such as ALK(F1174l), (ii) 
kinase-dead ALK mutants, e.g. ALK(I1250T) (Schönherr et al., 2011a) and (iii) 
ALK mutations that are ligand-dependent in nature. Irrespective of the nature of 
the observed ALK mutants, in every case the activity of the mutant ALK receptors 
could be abrogated by the ALK inhibitor crizotinib (Xalkori/PF-02341066), albeit 
with differing levels of sensitivity.