ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma

作者：Bresler Scott C; Weiser Daniel A; Huwe Peter J; Park Jin H; Krytska Kateryna; Ryles Hannah; Laudenslager Marci; Rappaport Eric F; Wood Andrew C; McGrady Patrick W; Hogarty Michael D; London Wendy B; Radhakrishnan Ravi; Lemmon Mark A^*; Mosse Yael P

来源：Cancer Cell, 2014, 26(5): 682-694.

DOI：10.1016/j.ccell.2014.09.019

Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples-at three hot spots and 13 minor sites-and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from nononcogenic mutations and allowed robust computational prediction of their effects. The mutated variants also showed differential in vitro crizotinib sensitivities. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma and will allow tailoring of ALK-targeted therapy to specific mutations.

• 出版日期2014-11-10