Phosphoproteome and gene expression profiling of ALK inhibition in neuroblastoma cell lines reveals conserved oncogenic pathways

Sci Signal. 2018 Nov 20;11(557):eaar5680. doi: 10.1126/scisignal.aar5680.


Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor that is a clinical target of major interest in cancer. Mutations and rearrangements in ALK trigger the activation of the encoded receptor and its downstream signaling pathways. ALK mutations have been identified in both familial and sporadic neuroblastoma cases as well as in 30 to 40% of relapses, which makes ALK a bona fide target in neuroblastoma therapy. Tyrosine kinase inhibitors (TKIs) that target ALK are currently in clinical use for the treatment of patients with ALK-positive non-small cell lung cancer. However, monotherapy with the ALK inhibitor crizotinib has been less encouraging in neuroblastoma patients with ALK alterations, raising the question of whether combinatorial therapy would be more effective. In this study, we established both phosphoproteomic and gene expression profiles of ALK activity in neuroblastoma cells exposed to first- and third-generation ALK TKIs, to identify the underlying molecular mechanisms and identify relevant biomarkers, signaling networks, and new therapeutic targets. This analysis has unveiled various important leads for novel combinatorial treatment strategies for patients with neuroblastoma and an increased understanding of ALK signaling involved in this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase / antagonists & inhibitors*
  • Anaplastic Lymphoma Kinase / metabolism
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Crizotinib / pharmacology
  • Dual-Specificity Phosphatases / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mass Spectrometry
  • Mitogen-Activated Protein Kinase Phosphatases / metabolism
  • Neuroblastoma / metabolism*
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • Protein Interaction Mapping
  • Protein Kinase Inhibitors / pharmacology*
  • Proteome*
  • Proteomics
  • RNA, Small Interfering / metabolism
  • Receptor, Insulin / metabolism
  • Sequence Analysis, RNA
  • Signal Transduction


  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • Proteome
  • RNA, Small Interfering
  • Crizotinib
  • Anaplastic Lymphoma Kinase
  • Receptor, Insulin
  • Mitogen-Activated Protein Kinase Phosphatases
  • Phosphoric Monoester Hydrolases
  • DUSP4 protein, human
  • Dual-Specificity Phosphatases