Anaplastic lymphoma kinase (ALK) inhibitor response in neuroblastoma is highly correlated with ALK mutation status, ALK mRNA and protein levels

Floor A M Duijkers, José Gaal, Jules P P Meijerink, Pieter Admiraal, Rob Pieters, Ronald R de Krijger, Max M van Noesel

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: In pediatric neuroblastoma (NBL), high anaplastic lymphoma kinase (ALK) levels appear to be correlated with an unfavorable prognosis, regardless of ALK mutation status. This suggests a therapeutic role for ALK inhibitors in NBL patients. We examined the correlation between levels of ALK, phosphorylated ALK (pALK) and downstream signaling proteins and response to ALK inhibition in a large panel of both ALK mutated and wild type (WT) NBL cell lines.

METHODS: We measured protein levels by western blot and ALK inhibitor sensitivity (TAE684) by viability assays in 19 NBL cell lines of which 6 had a point mutation and 4 an amplification of the ALK gene.

RESULTS: ALK 220 kDa (p = 0.01) and ALK 140 kDa (p = 0.03) protein levels were higher in ALK mutant than WT cell lines. Response to ALK inhibition was significantly correlated with ALK protein levels (p < 0.01). ALK mutant cell lines (n = 4) were 14,9 fold (p < 0,01) more sensitive to ALK inhibition than eight WT cell lines.

CONCLUSION: NBL cell lines often express ALK at high levels and are responsive to ALK inhibitors. Mutated cell lines express ALK at higher levels, which may define their superior response to ALK inhibition.

Original languageEnglish
Pages (from-to)409-17
Number of pages9
JournalCellular oncology (Dordrecht)
Volume34
Issue number5
DOIs
Publication statusPublished - May 2011
Externally publishedYes

Keywords

  • Anaplastic Lymphoma Kinase
  • Cell Differentiation/drug effects
  • Cell Line, Tumor
  • Cell Survival/drug effects
  • Extracellular Signal-Regulated MAP Kinases/metabolism
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic/drug effects
  • Humans
  • Mutation/genetics
  • Neuroblastoma/drug therapy
  • Neurons/drug effects
  • Phosphorylation/drug effects
  • Protein Kinase Inhibitors/pharmacology
  • Pyrimidines/pharmacology
  • RNA, Messenger/genetics
  • Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
  • Schwann Cells/drug effects
  • Signal Transduction/drug effects

Fingerprint

Dive into the research topics of 'Anaplastic lymphoma kinase (ALK) inhibitor response in neuroblastoma is highly correlated with ALK mutation status, ALK mRNA and protein levels'. Together they form a unique fingerprint.

Cite this