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

Authors
  • Chen, Lindi
  • Humphreys, Angharad
  • Turnbull, Lisa
  • Bellini, Angela
  • Gudrun Schleiermacher
  • Salwen, Helen
  • Cohn, Susan L.
  • Bown, Nick
  • Tweddle, Deborah A.
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
Jul 09, 2016
Volume
7
Issue
52
Pages
87301–87311
Identifiers
DOI: 10.18632/oncotarget.13541
PMID: 27888620
PMCID: PMC5349989
Source
USPC - SET - SVS
License
Green

Abstract

Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor kinase that belongs to the insulin receptor superfamily and has previously been shown to play a role in cell proliferation, migration and invasion in neuroblastoma. Activating ALK mutations are reported in both hereditary and sporadic neuroblastoma tumours, and several ALK inhibitors are currently under clinical evaluation as novel treatments for neuroblastoma. Overall, mutations at codons F1174, R1275 and F1245 together account for ∼85% of reported ALK mutations in neuroblastoma. NBLW and NBLW-R are paired cell lines originally derived from an infant with metastatic MYCN amplified Stage IVS (Evans Criteria) neuroblastoma, at diagnosis and relapse, respectively. Using both Sanger and targeted deep sequencing, this study describes the identification of distinct ALK mutations in these paired cell lines, including the rare R1275L mutation, which has not previously been reported in a neuroblastoma cell line. Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALK inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALK inhibitor induced apoptosis compared with NBLW cells. This pair of cell lines represents a valuable pre-clinical model of clonal evolution of ALK mutations associated with neuroblastoma progression.

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