Activating mutations in ALK provide a therapeutic target in neuroblastoma

  title={Activating mutations in ALK provide a therapeutic target in neuroblastoma},
  author={Rani E. George and Takaomi Sanda and Megan Hanna and Stefan Fr{\"o}hling and William Luther and Jianming Zhang and Yebin Ahn and Wenjun Zhou and Wendy B. London and Patrick W. McGrady and Liquan Xue and Sergey Zozulya and Vladim{\'i}r Gregor and Thomas R. Webb and Nathanael S. Gray and Dwight Gary Gilliland and Lisa R Diller and Heidi Greulich and Stephan W. Morris and Matthew L Meyerson and A. Thomas Look},
  pages={975 - 978}
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… 

Advanced Neuroblastoma: Role of ALK Mutations

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Identification of different ALK mutations in a pair of neuroblastoma cell lines established at diagnosis and relapse

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Oncogenic mutations of ALK in neuroblastoma

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Targeting MYCN and ALK in resistant and relapsing neuroblastoma

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Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update

This review will give a comprehensive overview on ALK inhibitors in clinical use in high-risk NBL and on the potential and limitations of novel inhibitors.

ALK inhibition with up-front chemotherapy in ALK-positive neuroblastoma patients

A mechanistic interaction in which ALK upregulates MYCN transcription is described, and clinical trials emerging to develop transcriptional inhibitors of MYCN, and to identify effective inhibitors of ALK in neuroblastoma patients are discussed.

Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells

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Defining Pathological Activities of ALK in Neuroblastoma, a Neural Crest-Derived Cancer

Neuroblastoma is a common extracranial solid tumour of childhood, responsible for 15% of cancer-related deaths in children. Prognoses vary from spontaneous remission to aggressive disease with

Characterization of rearrangements involving the ALK gene reveals a novel truncated form associated with tumor aggressiveness in neuroblastoma.

Results indicate that genomic rearrangements constitute an alternative mechanism to ALK point mutations resulting in receptor activation, and may be implicated in tumor aggressiveness.

Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients.

Interestingly, protein levels did not always correlate with ALK genetic alterations and/or mRNA abundance, however, wild-type ALK receptor requires a critical threshold of expression to achieve oncogenic activation.



Expression of the ALK tyrosine kinase gene in neuroblastoma.

Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer

It is shown that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells.

Development of anaplastic lymphoma kinase (ALK) small‐molecule inhibitors for cancer therapy

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EML4-ALK Fusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer

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Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.

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Lung cancer: Intragenic ERBB2 kinase mutations in tumours

The gene encoding the transmembrane protein tyrosine kinase ERBB2 (also known as HER2 or Neu) is sequenced from 120 primary lung tumours and 4% that have mutations within the kinase domain are identified.

The anaplastic lymphoma kinase in the pathogenesis of cancer

This Review will analyse how translocations or deregulated expression of ALK contribute to oncogenesis and how recent genetic or pharmacological tools, aimed at neutralizing its activity, can represent the basis for the design of powerful combination therapies.

Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma.

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