Abstract B151: Src inhibitor dasatinib reduces the metastatic phenotype of breast cancer cells.

Abstract

Abstract Subsequent to escaping the primary tumor, a successful metastatic tumor cell has to survive in the bloodstream, invade normal tissue at a secondary site, proliferate, and induce angiogenesis. Src is a non-receptor tyrosine kinase that is frequently over-expressed in malignances, and increased Src activity may be associated with poor patient prognosis. Src is well known to contribute to the metastatic phenotype of tumor cells through conferral of increased motility, migration, and invasion. Since these cellular functions are key components of the metastatic cascade, Src may be a novel target for breast cancer therapy. The present studies were undertaken to investigate whether molecular intervention in Src associated signaling could impact the metastatic phenotype of tumor cells. Specifically, we evaluated the in vitro and in vivo efficacy of the potent, selective and orally available Src inhibitor Dasatinib (BMS 354825) in the highly metastatic 4T1 murine mammary adenocarcinoma cell line. Dasatinib was evaluated in vitro for the ability to inhibit migration and invasion in the 4T1 cell line. The results showed that Dasatinib treatment (50–100 nM) significantly inhibited both migration and invasion in a dose dependent manner (6- to 10-fold for the doses studied). To examine the effect of Dasatinib on tumor cell-induced angiogenesis in vivo, an intradermal angiogenesis assay was used. Briefly, 4T1 tumor cells were inoculated intradermally on the ventral surface of athymic nude (Ncr nu/nu) mice and 3 days later the mice were euthanized and skin flaps were removed for visual quantification of the number of blood vessels intersecting each inoculate. Mice received daily doses of either Dasatinib (5 to 15 mg/kg) or vehicle by oral gavage. The results showed that Dasatinib treatment inhibited 4T1 tumor cell-induced angiogenesis by up to 60%. In summary, Dasatinib was found to significantly inhibit multiple cell functions critical to the successful dissemination of 4T1 breast cancer cells. The results suggest that Dasatinib may be useful in the reduction of breast cancer metastasis, and studies examining its impact on 4T1 metastases formation are currently ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B151.