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Nature DOI:10.1038/nature07397

Activating mutations in ALK provide a therapeutic target in neuroblastoma.

Publication TypeJournal Article
Year of Publication2008
AuthorsGeorge, RE, Sanda, T, Hanna, M, Fröhling, S, Luther, W, Zhang, J, Ahn, Y, Zhou, W, London, WB, McGrady, P, Xue, L, Zozulya, S, Gregor, VE, Webb, TR, Gray, NS, D Gilliland, G, Diller, L, Greulich, H, Morris, SW, Meyerson, M, A Look, T
Date Published2008 Oct 16
KeywordsAlleles, Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cell Survival, Enzyme Activation, Genome, Human, Humans, In Situ Hybridization, Fluorescence, In Situ Nick-End Labeling, Mice, Mutation, Neuroblastoma, Polymorphism, Single Nucleotide, Protein Structure, Tertiary, Protein-Tyrosine Kinases, Receptor Protein-Tyrosine Kinases, Sequence Analysis, DNA

Neuroblastoma, an embryonal tumour of the peripheral sympathetic nervous system, accounts for approximately 15% of all deaths due to childhood cancer. High-risk neuroblastomas are rapidly progressive; even with intensive myeloablative chemotherapy, relapse is common and almost uniformly fatal. Here we report the detection of previously unknown mutations in the ALK gene, which encodes a receptor tyrosine kinase, in 8% of primary neuroblastomas. Five non-synonymous sequence variations were identified in the kinase domain of ALK, of which three were somatic and two were germ line. The most frequent mutation, F1174L, was also identified in three different neuroblastoma cell lines. ALK complementary DNAs encoding the F1174L and R1275Q variants, but not the wild-type ALK cDNA, transformed interleukin-3-dependent murine haematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to the small-molecule inhibitor of ALK, TAE684 (ref. 4). Furthermore, two human neuroblastoma cell lines harbouring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis as measured by TdT-mediated dUTP nick end labelling (TUNEL). Short hairpin RNA (shRNA)-mediated knockdown of ALK expression in neuroblastoma cell lines with the F1174L mutation also resulted in apoptosis and impaired cell proliferation. Thus, activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumours and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibition with small molecules, providing a molecular rationale for targeted therapy of this disease.


Alternate JournalNature
PubMed ID18923525
PubMed Central IDPMC2587486
Grant ListK08 NS047983-05 / NS / NINDS NIH HHS / United States
K08 NS047983-04 / NS / NINDS NIH HHS / United States
R01 CA069129 / CA / NCI NIH HHS / United States
CA21765 / CA / NCI NIH HHS / United States
P30 CA021765 / CA / NCI NIH HHS / United States
K08 NS047983-03 / NS / NINDS NIH HHS / United States
CA69129 / CA / NCI NIH HHS / United States
K08 NS047983 / NS / NINDS NIH HHS / United States