SKI-606, a Src inhibitor, reduces tumor growth, invasion, and distant metastasis in a mouse model of thyroid cancer.

KIM WON GU; GUIGON CELINE; FOZZATTI LAURA; PARK JEONG; LU CHANGXUE ; WILLINGHAM MARK; CHENG SHEUE-YANN

Houston

Congreso; The 94rd ANNUAL MEETING, ENDO 2012; 2012

The Endocrine Society

Currently, no effective treatment for patients with radioiodine-refractory, advanced differentiated thyroid cancer is available. Novel treatment modalities are being actively sought. Aberrant activation of the Src pathway is associated with aggressive thyroid cancer. We hypothesized that inhibition of the Src pathway could prevent thyroid cancer progression and distant metastasis. The ThrbPV/PVmouse, harboring a knock-in dominantly negative mutation of the thyroid hormone receptor b gene (denoted as ThrbPV), spontaneously develops metastatic thyroid cancer. In this mouse model, we found that an over-activated Src pathway promotes thyroid carcinogenesis. For this study, we evaluated the effects of SKI-606, a potent inhibitor of Src, on thyroid carcinogenesis of ThrbPV/PVPten+/- mice, which were generated by haploid deficiency of the tumor suppressor gene Pten. These mice exhibited a more aggressive cancer phenotype with decreased survival, thus shortening the time for preclinical studies. SKI-606 treatment effectively inhibited aberrant activation of Src and its downstream targets to markedly inhibit the growth of thyroid tumor by 37%, thereby significantly increasing the survival of SKI-606-treated mice by 1.2 months as compared with vehicle-treated mice. Src inhibition reduced cell proliferation (38%) as evidenced by the 50% reduction in Ki-67 nuclear staining. SKI-606 treatment decreased the expression of key regulators of cell cycle progression, including cyclin B1 (85%), cyclin D1 (57%), cyclin E (57%), CDK4 (93%), CDK6 (38%), phosphorylated-Rb (75%), and E2F1 (93%). Importantly, SKI-606 treatment decreased vascular invasion (26%), and lung metastasis (45%) of thyroid cancer by inhibiting epithelial-mesenchymal transition via increased expression of E-cadeherin (2.2-fold) and decreased expression of vimentin (94%), slug (81%), MMP-2 (53%), and MMP-9 (89%). SKI-606 treatment also dramatically prevented de-differentiation by maintaining the normal follicular structure and expression of PAX8 and NIS differentiation markers via down-regulation of MAPK pathways. This preclinical study showed that for the first time, blocking of Src activity delays tumor progression and inhibits metastasis. Thus, Src and its downstream effectors are potential molecular targets for treatment of thyroid cancer. Importantly, oral SKI-606 is a promising treatment strategy for single-drug therapy or in combination with radioiodine therapy to treat refractory thyroid cancer.