Identification of different ALK mutations in a pair of neuroblastoma cell lines established at diagnosis and relapse
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Lindi Chen1, Angharad Humphreys2, Lisa Turnbull2, Angela Bellini3, Gudrun Schleiermacher3, Helen Salwen4, Susan L. Cohn4, Nick Bown2, Deborah A. Tweddle1
1Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom
2Northern Genetics Service, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Genetic Medicine, Central Parkway, Newcastle upon Tyne, NE1 3BZ, United Kingdom
3Institut Curie, 26 rue d’Ulm, 75248 Paris cedex 05, France
4Department of Pediatrics, University of Chicago, Chicago, Illinois 60637, USA
Deborah A. Tweddle, email: [email protected]
Keywords: neuroblastoma, ALK, R1275L, F1174L, paired cell lines
Received: April 20, 2016 Accepted: November 06, 2016 Published: November 24, 2016
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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