Cancer Therapy: Preclinical SKI-606, an Src Inhibitor, Reduces Tumor Growth, Invasion, and Distant Metastasis in a Mouse Model of Thyroid Cancer

Purpose: Src is overexpressed or hyperactivated in a variety of human cancers, including thyroid carcinoma. Src is a central mediator in multiple signaling pathways that are important in oncogenesis and cancer progression. In this study, we evaluated the effects of an Src inhibitor, SKI-606 (bosutinib), in a spontaneous metastatic thyroid cancer model with constitutively activated Src (ThrbPV/PVPtenþ/ mice). Experimental Design: ThrbPV/PVPtenþ/ mice were treated with SKI-606 or vehicle controls, beginning at 6 weeks of age until the mice succumbed to thyroid cancer. We assessed the effects of SKI-606 on thyroid cancer progression and analyzed the impact of SKI-606 on aberrant Src-mediated signaling. Results: SKI-606 effectively inhibited aberrant activation of Src and its downstream targets to markedly inhibit the growth of thyroid tumor, thereby prolonging the survival of treated mice. While Src inhibition did not induce cell apoptosis, it decreased cell proliferation by affecting the expression of key regulators of cell-cycle progression. Importantly, SKI-606 dramatically prevented dedifferentiation, vascular invasion, and lungmetastasis of thyroid cancer cells. These responses weremeditated by downregulation ofmitogenactivated protein kinase pathways and inhibition of the epithelial–mesenchymal transition. Conclusions: Our findings suggest that Src is critical in the progression of thyroid cancer, making oral SKI-606 a promising treatment strategy for refractory thyroid cancer. Clin Cancer Res; 18(5); 1281–90.