Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> The effects of dasatinib on thyroid cancer growth, signaling, cell cycle, and apoptosis were evaluated <i>in vitro</i>. The therapeutic efficacy of dasatinib was further tested <i>in vivo</i> 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.</p><p><b>Results:</b> 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% (<i>P</i> = 0.0014). Adjuvant and posttreatment approaches with dasatinib significantly inhibited metastasis (<i>P</i> = 0.016 and <i>P</i> = 0.004, respectively).</p><p><b>Conclusion:</b> 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. <i>Clin Cancer Res; 18(13); 3580–91. ©2012 AACR</i>.</p></div>

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