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

Won Gu Kim, Celine J. Guigon, Laura Fozzatti, Jeong Won Park, Changxue Lu, Mark C. Willingham, Sheue Yann Cheng

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)1281-1290
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number5
DOIs
StatePublished - Mar 1 2012
Externally publishedYes

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Thyroid Neoplasms
Neoplasm Metastasis
Growth
Neoplasms
Epithelial-Mesenchymal Transition
bosutinib
Mouth Neoplasms
Protein Kinases
Blood Vessels
Cell Cycle
Thyroid Gland
Carcinogenesis
Research Design
Down-Regulation
Cell Proliferation
Apoptosis
Lung
Survival

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 journalArticle

Kim, Won Gu ; Guigon, Celine J. ; Fozzatti, Laura ; Park, Jeong Won ; Lu, Changxue ; Willingham, Mark C. ; Cheng, Sheue Yann. / SKI-606, an Src inhibitor, reduces tumor growth, invasion, and distant metastasis in a mouse model of thyroid cancer. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 5. pp. 1281-1290.
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