title: Anaplastic lymphoma kinase (ALK) inhibitor response in neuroblastoma is highly correlated with ALK mutation status, ALK mRNA and protein levels.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatric Oncology-Hematology, Erasmus MC- Sophia Children's Hospital, Dr. Molewaterplein 60, 3015 GJ, Rotterdam, The Netherlands. f.duijkers@erasmusmc.nl
authors.forename: Floor A M
authors.initials: FA
authors.lastname: Duijkers
authors.forename: José
authors.initials: J
authors.lastname: Gaal
authors.forename: Jules P P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: Pieter
authors.initials: P
authors.lastname: Admiraal
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Max M
authors.initials: MM
authors.lastname: van Noesel
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C516714:NVP-TAE684; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases