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

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

doi:10.1016/j.ccell.2014.09.019

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

Scott C. Bresler, Daniel A. Weiser, Peter J. Huwe, Jin H. Park, Kateryna Krytska, Hannah Ryles, Marci Laudenslager, Eric F. Rappaport, Andrew C. Wood, Patrick W. McGrady, Michael D. Hogarty, Wendy B. London, Ravi Radhakrishnan, Mark A. Lemmon, Yaël P. Mossé

Research output: Contribution to journal › Article › peer-review

281 Scopus citations

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.

Original language	English (US)
Pages (from-to)	682-694
Number of pages	13
Journal	Cancer Cell
Volume	26
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2014.09.019
State	Published - Nov 10 2014
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2014.09.019

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Bresler, S. C., Weiser, D. A., Huwe, P. J., Park, J. H., Krytska, K., Ryles, H., Laudenslager, M., Rappaport, E. F., Wood, A. C., McGrady, P. W., Hogarty, M. D., London, W. B., Radhakrishnan, R., Lemmon, M. A., & Mossé, Y. P. (2014). ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma. Cancer Cell, 26(5), 682-694. https://doi.org/10.1016/j.ccell.2014.09.019

Bresler, SC, Weiser, DA, Huwe, PJ, Park, JH, Krytska, K, Ryles, H, Laudenslager, M, Rappaport, EF, Wood, AC, McGrady, PW, Hogarty, MD, London, WB, Radhakrishnan, R, Lemmon, MA & Mossé, YP 2014, 'ALK Mutations Confer Differential Oncogenic Activation and Sensitivity to ALK Inhibition Therapy in Neuroblastoma', Cancer Cell, vol. 26, no. 5, pp. 682-694. https://doi.org/10.1016/j.ccell.2014.09.019

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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 = "Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",

year = "2014",

month = nov,

day = "10",

doi = "10.1016/j.ccell.2014.09.019",

language = "English (US)",

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AU - Bresler, Scott C.

AU - Weiser, Daniel A.

AU - Huwe, Peter J.

AU - Park, Jin H.

AU - Krytska, Kateryna

AU - Ryles, Hannah

AU - Laudenslager, Marci

AU - Rappaport, Eric F.

AU - Wood, Andrew C.

AU - McGrady, Patrick W.

AU - Hogarty, Michael D.

AU - London, Wendy B.

AU - Radhakrishnan, Ravi

AU - Lemmon, Mark A.

AU - Mossé, Yaël P.

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N2 - 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.

AB - 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.

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

Abstract

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UN SDGs

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