Abstract
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 (Thrb PV/PVPten +/- mice). Experimental Design: Thrb PV/PVPten +/- 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 lung metastasis of thyroid cancer cells. These responses were meditated by downregulation of mitogenactivated 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1281-1290 |
| Number of pages | 10 |
| Journal | Clinical Cancer Research |
| Volume | 18 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 1 2012 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
SKI-606, an Src inhibitor, reduces tumor growth, invasion, and distant metastasis in a mouse model of thyroid cancer. / Kim, Won Gu; Guigon, Celine J.; Fozzatti, Laura; Park, Jeong Won; Lu, Changxue; Willingham, Mark C.; Cheng, Sheue Yann.
In: Clinical Cancer Research, Vol. 18, No. 5, 01.03.2012, p. 1281-1290.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - SKI-606, an Src inhibitor, reduces tumor growth, invasion, and distant metastasis in a mouse model of thyroid cancer
AU - Kim, Won Gu
AU - Guigon, Celine J.
AU - Fozzatti, Laura
AU - Park, Jeong Won
AU - Lu, Changxue
AU - Willingham, Mark C.
AU - Cheng, Sheue Yann
PY - 2012/3/1
Y1 - 2012/3/1
N2 - 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 (Thrb PV/PVPten +/- mice). Experimental Design: Thrb PV/PVPten +/- 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 lung metastasis of thyroid cancer cells. These responses were meditated by downregulation of mitogenactivated 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.
AB - 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 (Thrb PV/PVPten +/- mice). Experimental Design: Thrb PV/PVPten +/- 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 lung metastasis of thyroid cancer cells. These responses were meditated by downregulation of mitogenactivated 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.
UR - http://www.scopus.com/inward/record.url?scp=84863238702&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863238702&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-11-2892
DO - 10.1158/1078-0432.CCR-11-2892
M3 - Article
C2 - 22271876
AN - SCOPUS:84863238702
VL - 18
SP - 1281
EP - 1290
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 5
ER -