title: Global tyrosine kinome profiling of human thyroid tumors identifies Src as a promising target for invasive cancers.
abstract: BACKGROUND
  Novel therapies are needed for the treatment of invasive thyroid cancers. Aberrant activation of tyrosine kinases plays an important role in thyroid oncogenesis. Because current targeted therapies are biased toward a small subset of tyrosine kinases, we conducted a study to reveal novel therapeutic targets for thyroid cancer using a bead-based, high-throughput system.
  
  
  METHODS
  Thyroid tumors and matched normal tissues were harvested from twenty-six patients in the operating room. Protein lysates were analyzed using the Luminex immunosandwich, a bead-based kinase phosphorylation assay. Data was analyzed using GenePattern 3.0 software and clustered according to histology, demographic factors, and tumor status regarding capsular invasion, size, lymphovascular invasion, and extrathyroidal extension. Survival and invasion assays were performed to determine the effect of Src inhibition in papillary thyroid cancer (PTC) cells.
  
  
  RESULTS
  Tyrosine kinome profiling demonstrated upregulation of nine tyrosine kinases in tumors relative to matched normal thyroid tissue: EGFR, PTK6, BTK, HCK, ABL1, TNK1, GRB2, ERK, and SRC. Supervised clustering of well-differentiated tumors by histology, gender, age, or size did not reveal significant differences in tyrosine kinase activity. However, supervised clustering by the presence of invasive disease showed increased Src activity in invasive tumors relative to non-invasive tumors (60% v. 0%, p<0.05). In vitro, we found that Src inhibition in PTC cells decreased cell invasion and proliferation.
  
  
  CONCLUSIONS
  Global kinome analysis enables the discovery of novel targets for thyroid cancer therapy. Further investigation of Src targeted therapy for advanced thyroid cancer is warranted.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA. nlcho@partners.org
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Cho
authors.forename: Chi-Iou
authors.initials: CI
authors.lastname: Lin
authors.forename: Jinyan
authors.initials: J
authors.lastname: Du
authors.forename: Edward E
authors.initials: EE
authors.lastname: Whang
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ito
authors.forename: Francis D
authors.initials: FD
authors.lastname: Moore
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Ruan
mesh_terms: D000231:Adenocarcinoma, Papillary / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D049109:Cell Proliferation; D000069439:Dasatinib; D057166:High-Throughput Screening Assays; D006801:Humans; D055442:Metabolome; D058990:Molecular Targeted Therapy; D009154:Mutation; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*; D015854:Up-Regulation; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D014443:Tyrosine; D019061:src-Family Kinases; D000069439:Dasatinib