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

Lookup NU author(s): Dr Lindi Chen, Angharad Humphreys, Dr Lisa Turnbull, Dr Nicholas Bown, Professor Deborah Tweddle

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Chen L, Humphreys A, Turnbull L, Bellini A, Schleiermacher G, Salwen H, Cohn SL, Bown N, Tweddle DA

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2016

Volume: 7

Pages: 87301-87311

Online publication date: 24/11/2016

Acceptance date: 06/11/2016

ISSN (electronic): 1949-2553

Publisher: Impact Journal LLC

URL: http://dx.doi.org/10.18632/oncotarget.13541

DOI: 10.18632/oncotarget.13541

PubMed id: 27888620


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