title: Targeted inhibition of Src kinase with dasatinib blocks thyroid cancer growth and metastasis.
abstract: OBJECTIVE
  There are no effective therapies for patients with poorly differentiated papillary thyroid cancer (PTC) or anaplastic thyroid cancer (ATC), and metastasis to the bone represents a significantly worse prognosis. Src family kinases (SFKs) are overexpressed and activated in numerous tumor types and have emerged as a promising therapeutic target, especially in relation to metastasis. We recently showed that Src is overexpressed and activated in thyroid cancer. We therefore tested whether inhibition of Src with dasatinib (BMS-354825) blocks thyroid cancer growth and metastasis.
  
  
  METHODS
  The effects of dasatinib on thyroid cancer growth, signaling, cell cycle, and apoptosis were evaluated in vitro. The therapeutic efficacy of dasatinib was further tested in vivo using an orthotopic and a novel experimental metastasis model. Expression and activation of SFKs in thyroid cancer cells was characterized, and selectivity of dasatinib was determined using an Src gatekeeper mutant.
  
  
  RESULTS
  Dasatinib treatment inhibited Src signaling, decreased growth, and induced cell-cycle arrest and apoptosis in a subset of thyroid cancer cells. Immunoblotting showed that c-Src and Lyn are expressed in thyroid cancer cells and that c-Src is the predominant SFK activated. Treatment with dasatinib blocked PTC tumor growth in an orthotopic model by more than 90% (P = 0.0014). Adjuvant and posttreatment approaches with dasatinib significantly inhibited metastasis (P = 0.016 and P = 0.004, respectively).
  
  
  CONCLUSIONS
  These data provide the first evidence that Src is a central mediator of thyroid cancer growth and metastasis, indicating that Src inhibitors may have a higher therapeutic efficacy in thyroid cancer, as both antitumor and antimetastatic agents.
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Chan
authors.forename: Xia
authors.initials: X
authors.lastname: Jing
authors.forename: Laura A
authors.initials: LA
authors.lastname: Pike
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhou
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Lim
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Sams
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Lund
authors.forename: Vibha
authors.initials: V
authors.lastname: Sharma
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Haugen
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Schweppe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000201:enzymology / Q000517:prevention & control* / Q000556:secondary; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D013844:Thiazoles; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; D000069439:Dasatinib