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Targeting Src Family Kinases Inhibits Growth and Lymph Node Metastases of Prostate Cancer in an Orthotopic Nude Mouse Model

¹ The Program in Cancer Biology, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston; and Departments of ² Cancer Biology, ³ Surgical Oncology, ⁴ Genitourinary Medical Oncology, and ⁵ Experimental Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Gary E. Gallick, Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Box 173, 1515 Holcombe Boulevard, Houston TX 77030. Phone: 713-563-4919; Fax: 713-563-5489; E-mail: ggallick{at}mdanderson.org.

Key Words: Prostate cancer • Lymph node • Metastasis • Src family kinase • Dasatinib

Aberrant expression and/or activity of members of the Src family of nonreceptor protein tyrosine kinases (SFK) are commonly observed in progressive stages of human tumors. In prostate cancer, two SFKs (Src and Lyn) have been specifically implicated in tumor growth and progression. However, there are no data in preclinical models demonstrating potential efficacy of Src inhibitors against prostate cancer growth and/or metastasis. In this study, we used the small molecule SFK/Abl kinase inhibitor dasatinib, currently in clinical trials for solid tumors, to examine in vitro and in vivo effects of inhibiting SFKs in prostate tumor cells. In vitro, dasatinib inhibits both Src and Lyn activity, resulting in decreased cellular proliferation, migration, and invasion. In orthotopic nude mouse models, dasatinib treatment effectively inhibits expression of activated SFKs, resulting in inhibition of both tumor growth and development of lymph node metastases in both androgen-sensitive and androgen-resistant tumors. In primary tumors, SFK inhibition leads to decreased cellular proliferation (determined by immunohistochemistry for proliferating cell nuclear antigen). In vitro, small interfering RNA (siRNA)–mediated inhibition of Lyn affects cellular proliferation; siRNA inhibition of Src affects primarily cellular migration. Therefore, we conclude that SFKs are promising therapeutic targets for treatment of human prostate cancer and that Src and Lyn activities affect different cellular functions required for prostate tumor growth and progression. [Cancer Res 2008;68(9):3323–33]

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