A Src/Abl Kinase Inhibitor, SKI-606, Blocks Breast Cancer Invasion, Growth, and Metastasis In vitro and In vivo

Abstract

The central role of Src in the development of several malignancies, including breast cancer, and the accumulating evidence of its interaction with receptor tyrosine kinases, integrins, and steroid receptors have identified it as an attractive therapeutic target. In the current study, we have evaluated the effect of a Src/Abl kinase inhibitor, SKI-606, on breast cancer growth, migration, invasion, and metastasis. Treatment of human breast cancer cells MDA-MB-231 with SKI-606 caused a marked inhibition of cell proliferation, invasion, and migration by inhibiting mitogen-activated protein kinase and Akt phosphorylation. For in vivo studies, MDA-MB-231 cells transfected with the plasmid encoding green fluorescent protein (GFP; MDA-MB-231-GFP) were inoculated into the mammary fat pads of female BALB/c nu/nu mice. Once tumor volume reached 30 to 50 mm 3 , animals were randomized and treated with vehicle alone or 150 mg/kg SKI-606 by daily oral gavage. Experimental animals receiving SKI-606 developed tumors of significantly smaller volume (45-54%) compared with control animals receiving vehicle alone. Analysis of lungs, liver, and spleen of these animals showed a significant decrease in GFP-positive tumor metastasis in animals receiving SKI-606 at a dose that was well tolerated. Western blot analysis and immunohistochemical analysis of primary tumors showed that these effects were due to the ability of SKI-606 to block tumor cell proliferation, angiogenesis, growth factor expression, and inhibition of Src-mediated signaling pathways in vivo. Together, the results from these studies provide compelling evidence for the role of Src inhibitors as therapeutic agents for blocking breast cancer growth and metastasis. [Cancer Res 2007;67(4):1580-8] IntroductionSrc belongs to a non-receptor tyrosine kinase family that comprises nine members in vertebrates (1). It is overexpressed in several human cancers, including carcinomas of the breast, lung, colon, esophagus, skin, parotid, cervix, as well as gastric tissues (2-4). For breast cancer, increased Src activity is believed to play an important role in its development and progression. Furthermore, elevated expression of Src has been associated with poor prognosis (2). Src plays a role in several signaling pathways that are involved in cell proliferation and survival (5). Additionally, the ability of Src to promote tumor cell invasion can lead to the development of tumor metastasis (6). Collectively, Src plays a major role in regulating important mechanisms of specific receptor pathways where their activation can influence the biological activities of the tumor cell (1).In the vascular endothelial growth factor (VEGF) signaling pathway, phosphorylation of VE-cadherin on Tyr 685 by Src plays a pivotal role in regulating VE-cadherin adhesive activity (7). In addition, Src has been shown to regulate phosphatidylinositol 3-kinase and Akt pathways (8). Several growth factors and proteases, including parathyroid hormone-related protein (PTHrP) and urokinase-type plasminogen...

Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts

“…1B). This is consistent with previously published studies of bosutinib in colorectal xenografts (24) and breast xenografts (25) as well as other Src inhibitors in pancreas cancer mouse models (14).…”

Current Status of Src Inhibitors in Solid Tumor Malignancies

“…It displays 200-fold more potent inhibition of Bcr-Abl than imatinib. In breast cancer cell lines, bosutinib was shown to reduce cell proliferation, invasion, and migration by inhibiting mitogen-activated protein kinase and Akt phosphorylation [83]. In colorectal cancer, bosutinib also promoted cytosolic localization of ␤-catenin, leading to greater binding affinity to E-cadherin, resulting in greater adhesion of colorectal cancer cells and less mo- Advanced/metastatic disease; may be previously treated unless otherwise noted.…”

c-Abl regulates estrogen receptor α transcription activity through its stabilization by phosphorylation

“…The activated forms of Abl kinases (BCR-Abl, Tel-Abl and Tel-Arg) induce the development of human leukemia (Skorski et al, 1998;Druker et al, 2001;Pendergast, 2001;Kim et al, 2004). Recent studies suggest that Abl kinases are constitutively activated in breast cancer cells and constitutive activation of Abl kinases promotes breast cancer cell invasion (Srinivasan and Plattner, 2006;Jallal et al, 2007;Srinivasan et al, 2008). Although the mechanism by which BCR-Abl drives leukemiagenesis is well understood, little is known regarding how Abl promotes progression of solid tumors.…”