@article{db48877c2ff04fc6a54451d67bc2f27a,
title = "ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma",
abstract = "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 13minor 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 invitro 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.",
author = "Bresler, {Scott C.} and Weiser, {Daniel A.} and Huwe, {Peter J.} and Park, {Jin H.} and Kateryna Krytska and Hannah Ryles and Marci Laudenslager and Rappaport, {Eric F.} and Wood, {Andrew C.} and McGrady, {Patrick W.} and Hogarty, {Michael D.} and London, {Wendy B.} and Ravi Radhakrishnan and Lemmon, {Mark A.} and Moss{\'e}, {Ya{\"e}l P.}",
note = "Funding Information: This work was supported in part by NIH Grant R01-CA140198 (to Y.P.M.), by U.S. Army Peer Reviewed Medical Research Program Grants W81XWH-10-1-0212/3 (to M.A.L. and Y.P.M), by European Commission Grant FP7-ICT-2011-9-600841 (to R.R.), by Predoctoral Fellowship 11PRE7670020 from the Great Rivers Affiliate of the American Heart Association (to J.H.P.), by NIH Training Grant in Structural Biology T32-GM008275 (to S.C.B), by an NSF graduate research fellowship (to P.J.H.), and by the Institute for Translational Medicine and Therapeutics of the University of Pennsylvania (supported by NCRR Grant UL1RR024134). Computational resources were provided in part by the National Partnership for Advanced Computational Infrastructure under Grant MCB060006 from XSEDE (to R.R.). We thank the members of the M.A.L., Y.P.M., Ferguson, and R.R. laboratories for valuable discussions and Pfizer for their gift of crizotinib. Y.P.M. is the inventor of a patent filed by the Children{\textquoteright}s Hospital of Philadelphia (WO/2009/103061 or PCT/US2009/034288: Methods and Compositions for Identifying, Diagnosing, and Treating Neuroblastoma). Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",
year = "2014",
month = nov,
day = "10",
doi = "10.1016/j.ccell.2014.09.019",
language = "English (US)",
volume = "26",
pages = "682--694",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",
}
