title: The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells.
abstract: BACKGROUND
  Medullary and papillary thyroid carcinoma (MTC and PTC) are two types of thyroid cancer that can originate from activating mutations or rearrangements in the RET gene. Therapeutic options are limited in recurrent disease, but because RET is a tyrosine kinase (TK) receptor involved in cellular growth and proliferation, treatment with a TK inhibitor might be promising. Several TK inhibitors have been tested in clinical trials, but it is unknown which inhibitor is most effective and whether there is any specificity for particular RET mutations.
  
  
  OBJECTIVE
  We aimed to compare the effect of four TK inhibitors (axitinib, sunitinib, vandetanib, and XL184) on cell proliferation, RET expression and autophosphorylation, and ERK activation in cell lines expressing a MEN2A (MTC-TT), a MEN2B (MZ-CRC-1) mutation, and a RET/PTC (TPC-1) rearrangement.
  
  
  METHODS
  The three cell lines were cultured and treated with the four TK inhibitors. Effects on cell proliferation and RET and ERK expression and activation were determined.
  
  
  RESULTS
  XL184 and vandetanib most effectively inhibited cell proliferation, RET autophosphorylation in combination with a reduction of RET expression, and ERK phosphorylation in MTC-TT and MZ-CRC-1, respectively. TPC-1 cells showed a decrease in RET autophosphorylation after treatment with XL184, but no effect was observed on ERK activation.
  
  
  CONCLUSIONS
  There is indeed specificity for different RET mutations, with XL184 being the most potent inhibitor in MEN2A and PTC and vandetanib the most effective in MEN2B in vitro. No TK inhibitor was superior for all the cell lines tested, indicating that mutation-specific therapies could be beneficial in treating MTC and PTC.
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Hans H G
authors.initials: HH
authors.lastname: Verbeek
authors.forename: Maria M
authors.initials: MM
authors.lastname: Alves
authors.forename: Jan-Willem B
authors.initials: JW
authors.lastname: de Groot
authors.forename: Jan
authors.initials: J
authors.lastname: Osinga
authors.forename: John T M
authors.initials: JT
authors.lastname: Plukker
authors.forename: Thera P
authors.initials: TP
authors.lastname: Links
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000077784:Axitinib; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000077210:Sunitinib; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000813:Anilides; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D011799:Quinazolines; C558660:cabozantinib; D000077784:Axitinib; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib; C452423:vandetanib