**9. ALK as a therapeutic target in NB**

Constitutive activation of the ALK receptor tyrosine kinase by mutation or translocation appears to contribute to the malignant phenotype of several cancers, including NB, making it a potentially therapeutic target [49]. Both wild type ALK and the F1174L-mutated ALK upregulate MYCN expression [50], and these two genes lead to constitutive phosphorylation of ALK and of downstream signaling molecules, PI3K/AKT/mTOR, that are critical for cell proliferation and survival [51]. ALKF1174L cosegregates with MYCN amplification in patients, and this combination is associated with a particularly poor prognosis, as shown by the fatal outcome of 9 of 10 children with ALKF1174L/MYCN-amplified tumors [52]. Targeting ALK with PI3K/Akt/mTOR inhibitors may inhibit cell growth in tumor lines with concomitant MYCN amplification.
