Differential Inhibitor Sensitivity of Anaplastic Lymphoma Kinase Variants Found in Neuroblastoma

摘要: Activating mutations in the anaplastic lymphoma kinase (ALK) gene were recently discovered neuroblastoma, a cancer of developing autonomic nervous system that is most commonly diagnosed malignancy first year life. The frequent ALK neuroblastoma cause amino acid substitutions (F1174L and R1275Q) intracellular tyrosine domain intact receptor. Identification as an oncogenic driver suggests crizotinib (PF-02341066), dual-specific inhibitor Met kinases, will be useful treating this malignancy. Here, we assessed ability to inhibit proliferation cell lines xenografts expressing mutated or wild-type ALK. Crizotinib inhibited either R1275Q-mutated amplified In contrast, harboring F1174L-mutated relatively resistant crizotinib. Biochemical analyses revealed reduced susceptibility inhibition resulted from increased adenosine triphosphate-binding affinity (as also seen acquired resistance epidermal growth factor receptor inhibitors). Thus, effect should surmountable with higher doses and/or higher-affinity inhibitors.