title: Thyroid cancer cell resistance to gefitinib depends on the constitutive oncogenic activation of the ERK pathway.
abstract: BACKGROUND
  Poorly differentiated thyroid carcinomas are refractory to common anticancer therapies, and novel inhibitors are being tested in these deadly malignancies. The epidermal growth factor receptor (EGFR) tyrosine kinase represents an attractive target for treatment because it is up-regulated in thyroid cancer and plays a role in cancer progression. However, EGFR inhibitors have provided poor results in thyroid carcinomas.
  
  
  OBJECTIVE
  We evaluated the possible mechanism underlying the resistance of thyroid cancer cells to EGFR inhibitors.
  
  
  METHODS
  We tested the effect of the EGFR tyrosine kinase inhibitor gefitinib in a panel of thyroid cancer cell lines.
  
  
  RESULTS
  We found that in most of the cell lines, although gefitinib inhibited EGFR phosphorylation, it was poorly effective in reducing cell viability. gefitinib, however, was able to inhibit epidermal growth factor-induced cell migration and matrix invasion. In most thyroid cancer cell lines, gefitinib significantly inhibited Akt phosphorylation by inhibiting EGFR activation, but it had limited or no effect on ERK phosphorylation. The poor cell response to gefitinib was associated with genetic alterations, leading to constitutive activation of the ERK pathway, including BRAF(V600E) and HRAS(G12A/Q61R) mutations and RET/PTC1 rearrangement. When BRAF(V600E)-positive thyroid cancer cells were incubated with the specific BRAF inhibitor PLX4032, sensitivity to gefitinib was restored. Similar results were obtained with rat sarcoma and RET/papillary thyroid cancer inhibitors.
  
  
  CONCLUSIONS
  These results indicate that thyroid cancer resistance to gefitinib is due to the constitutive activation of the mitogenic pathway by either signals downstream of EGFR or other tyrosine kinase receptors. This resistance can be overcome by the combined use of selective inhibitors.
authors.affiliation: Endocrinology Unit, Department of Clinical and Molecular Bio-Medicine, University of Catania, Garibaldi-Nesima Medical Center, Via Palermo 636, 95122 Catania, Italy. f.frasca@unict.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Frasca
authors.forename: Veronica
authors.initials: V
authors.lastname: Vella
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Nicolosi
authors.forename: Rosa Linda
authors.initials: RL
authors.lastname: Messina
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Gianì
authors.forename: Sonia
authors.initials: S
authors.lastname: Lotta
authors.forename: Paolo
authors.initials: P
authors.lastname: Vigneri
authors.forename: Concetto
authors.initials: C
authors.lastname: Regalbuto
authors.forename: Riccardo
authors.initials: R
authors.lastname: Vigneri
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D011905:Genes, ras; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009154:Mutation; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000077156:Gefitinib