Mutation-Independent Activation of the Anaplastic Lymphoma Kinase in Neuroblastoma.

Abstract

Activating mutations of anaplastic lymphoma kinase (ALK) have been identified as important players in neuroblastoma development. Our goal was to evaluate the significance of overall ALK activation in neuroblastoma. Expression of phosphorylated ALK, ALK, and its putative ligands, pleiotrophin and midkine, was screened in 289 neuroblastomas and 56 paired normal tissues. ALK was expressed in 99% of tumors and phosphorylated in 48% of cases. Pleiotrophin and midkine were expressed in 58% and 79% of tumors, respectively. ALK activation was significantly higher in tumors than in paired normal tissues, together with ALK and midkine expression. ALK activation was largely independent of mutations and correlated with midkine expression in tumors. ALK activation in tumors was associated with favorable features, including a younger age at diagnosis, hyperdiploidy, and detection by mass screening. Antitumor activity of the ALK inhibitor TAE684 was evaluated in wild-type or mutated ALK neuroblastoma cell lines and xenografts. TAE684 was cytotoxic in vitro in all cell lines, especially those harboring an ALK mutation. TAE684 efficiently inhibited ALK phosphorylation in vivo in both F1174I and R1275Q xenografts but demonstrated antitumor activity only against the R1275Q xenograft. In conclusion, ALK activation occurs frequently during neuroblastoma oncogenesis, mainly through mutation-independent mechanisms. However, ALK activation is not associated with a poor outcome and is not always a driver of cell proliferation and/or survival in neuroblastoma.

• Authors: Marie Regairaz, Fabienne Munier, Hervé Sartelet, Marine Castaing, Virginie Marty, Céline Renauleaud, Camille Doux, Jean Delbé, José Courty, Monique Fabre, Shigeru Ohta, Philippe Vielh, Stefan Michiels, Dominique Valteau-Couanet, Gilles Vassal
• Journal: The American journal of pathology (Am J Pathol) Vol. 186 Issue 2 Pg. 435-45 (02 2016) ISSN: 1525-2191 [Electronic] United States
• PMID: 26687816 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Pyridines
• ALK protein, human
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases

Topics

• Adolescent
• Anaplastic Lymphoma Kinase
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Cell Transformation, Neoplastic (drug effects, metabolism)
• Child
• Child, Preschool
• Female
• Humans
• Infant
• Infant, Newborn
• Male
• Mutation (genetics)
• Neuroblastoma (metabolism)
• Phosphorylation (genetics)
• Protein Kinase Inhibitors (pharmacology)
• Pyridines (pharmacology)
• Receptor Protein-Tyrosine Kinases (genetics, metabolism)
• Signal Transduction (drug effects)