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Cited by 893Neuroblastoma Research and TreatmentsNeurofibromatosis and Schwannoma CasesCongenital gastrointestinal and neural anomalies

Activating mutations in ALK provide a therapeutic target in neuroblastoma

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George, Rani E., Sanda, Takaomi, Hanna, Megan, Fröhling, Stefan, II, William Luther, Zhang, Jianming, Ahn, Yebin, Zhou, Wenjun +13 more·2008·Nature
DOI 10.1038/nature07397PMC PMC2587486
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Abstract

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.

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  • In neuroblastoma, frequent point mutation of the RTK anaplastic lymphoma kinase (ALK) in the kinase domain (F1174L) leads to constitutive activation of STAT3.

    “In neuroblastoma, frequent point mutation of the RTK anaplastic lymphoma kinase (ALK) in the kinase domain (F1174L) leads to constitutive activation of STAT3.50”

    From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [50]

    The paper reports F1174L as the most common ALK mutation in its primary neuroblastoma samples (4/93 tumors) and finds STAT3 phosphorylation in IL-3-deprived Ba/F3 cells engineered to express F1174L (passages 3 and 5, section labeled Abstract). It also reports reduced STAT3 phosphorylation after ALK inhibition in F1174L neuroblastoma cell lines (passage 4). It does not directly establish constitutive STAT3 activation caused by F1174L in neuroblastoma tumors. (LLM, conf=0.84)

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Research works printed but not linked: 20

  1. [2]Matthay KK Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid Children's Cancer Group N Engl J Med 1999 341 1165 1173 10519894
  2. [3]George RE High Risk Neuroblastoma Treated with Tandem Autologous Peripheral Blood Stem Cell-Supported Transplant: Long-term Survival Update J. Clin Oncol 2006 24 2891-289 16782928
  3. [4]Galkin AV Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK Proc Natl Acad Sci U S A 2007 104 270 275 17185414 PMC1765448
  4. [5]George RE Genome-wide analysis of neuroblastomas using high-density single nucleotide polymorphism arrays PLOS One 2007 2 e255 e264 17327916 PMC1797488
  5. [6]Morris SW Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma Science 1994 263 1281 1284 8122112
  6. [7]Soda M Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer Nature 2007 448 561 566 17625570
  7. [8]Rikova K Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer Cell 2007 131 1190 1203 18083107
  8. [9]Chiarle R Voena C Ambrogio C Piva R Inghirami G The anaplastic lymphoma kinase in the pathogenesis of cancer Nat Rev Cancer 2008 8 11 23 18097461
  9. [15]Jiang J Epidermal growth factor-independent transformation of Ba/F3 cells with cancer-derived epidermal growth factor receptor mutants induces gefitinib-sensitive cell cycle progression Cancer Res 2005 65 8968 8974 16204070
  10. [16]Fröhling S Identification of driver and passenger mutations of FLT3 by high-throughput DNA sequence analysis and functional assessment of candidate alleles Cancer Cell 2007 12 501 513 18068628
  11. [17]Koivunen JP EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer Clin Cancer Res 2008 14 4275 4283 18594010 PMC3025451
  12. [18]Li R Morris SW Development of anaplastic lymphoma kinase (ALK) small-molecule inhibitors for cancer therapy Med Res Rev 2008 28 372 412 17694547
  13. [19]McDermott U Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors Cancer Res 2008 68 3389 3395 18451166
  14. [20]Lamant L Expression of the ALK tyrosine kinase gene in neuroblastoma Am J Pathol 2000 156 1711 1721 10793082 PMC1876934
  15. [21]Miyake I Activation of anaplastic lymphoma kinase is responsible for hyperphosphorylation of ShcC in neuroblastoma cell lines Oncogene 2002 21 5823 5834 12185581
  16. [22]Osajima-Hakomori Y Biological role of anaplastic lymphoma kinase in neuroblastoma Am J Pathol 2005 167 213 222 15972965 PMC1603453
  17. [23]Stommel JM Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies Science 2007 318 287 290 17872411
  18. [25]Nakagawara A Differential expression of pleiotrophin and midkine in advanced neuroblastomas Cancer Res 1995 55 1792 1797 7712489
  19. [26]Calvet L Pleiotrophin, a candidate gene for poor tumor vasculature and in vivo neuroblastoma sensitivity to irinotecan Oncogene 2006 25 3150 3159 16501609
  20. [27]Nickerson DA Tobe VO Taylor SL PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing Nucleic Acids Res 1997 25 2745 2751 9207020 PMC146817

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Authors
George, R. E., Sanda, T., Hanna, M., Fröhling, S., II, W. L., Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., Gregor, V. E., Webb, T. R., Gray, N. S., Gilliland, D. G., Diller, L., Greulich, H., Morris, S. W., Meyerson, M., & Look, A. T.
Affiliations
  • Harvard University (US)
  • Broad Institute (US)
  • Brigham and Women's Hospital (US)
  • University of Florida (US)
  • ChemBridge (United States) (US)
  • St. Jude Children's Research Hospital (US)
Corresponding author
  • Meyerson, Matthew
  • Look, A. Thomas
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2008-10
Volume
455
Issue
7215
Pages
975-978
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature07397
PMC
PMC2587486
OpenAlex
W2060275730
Cited by
893
References
6
Citations by year
2026: 14 · 2025: 24 · 2024: 39 · 2023: 44 · 2022: 35 · 2021: 60 · 2020: 28 · 2019: 40 · 2018: 48 · 2017: 49 · 2016: 50 · 2015: 62 · 2014: 55 · 2013: 70 · 2012: 84
FWCI
41.07
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Cancer Institute (CA 69129, R01CA069129, CA21765, P30CA021765)
  • National Institute of Neurological Disorders and Stroke (K08NS047983)
Topics
  • Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
  • Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
  • Health Sciences › Medicine › Surgery › Congenital gastrointestinal and neural anomalies
Keywords
neuroblastoma, anaplastic lymphoma kinase, ALK mutations, kinase domain, somatic mutations, germline mutations, ALK inhibitors, TAE684, apoptosis, cell proliferation, tumorigenicity, therapeutic target, childhood cancer, shRNA
MeSH terms
Anaplastic Lymphoma Kinase, Alleles, Animals, Cell Survival, Enzyme Activation, Humans, Mutation, Neuroblastoma, Protein-Tyrosine Kinases, Genome, Human, Apoptosis, In Situ Hybridization, Fluorescence, Sequence Analysis, DNA, Protein Structure, Tertiary, In Situ Nick-End Labeling, Polymorphism, Single Nucleotide, Receptor Protein-Tyrosine Kinases, Cell Line, Tumor, Cell Proliferation, Mice

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