e14625 TKI258 (4-amino-5-fluor-3-[5-(4-metylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-one, formerly known as CHIR258) is an ATP-competitive inhibitor with activities against class III or IV receptor kinases, which include FGFR, VEGFR, PDGFR, FLT3, and KIT. It has been demonstrated to possess strong anti-tumor and anti-angiogenetic activities in different tumor models, and, therefore, this compound is currently being clinically assessed for the treatment of diverse malignancies. In this study, we chose the breast cancer cell line MDA-MB-231, a cell line with high invasive capacities, as an in vitro model to analyze the effect and functional mechanism of TKI258 on the breast cancer invasiveness. Treatment of MDA-MB-231 cells with TKI258 resulted in reduced invasive capacities in a dose-dependent manner. In association with this effect, we observed that TKI258 down-regulated the phosphorylation of ERK1/2 and STAT3 and inhibited the VEGF production in the cell supernatants. Most interestingly, we found TKI258 had influence on the inflammatory chemokines CCL5 and CCL2 level if MDA-MB-231 cells were co-cultured with breast cancer stroma cells. We found that CCL5/CCL2 mRNA level in MDA-MB-231 cells, in stroma cells, or in co-culture of MDA-MB-231/breast cancer stroma was strongly inhibited by TKI258 as detected with real-time PCR. Parallel to this result, the dramatically elevated CCL2/CCL5 level in the media supernatants from co-cultured MDA-MB-231/stroma cells was reduced by TKI258 effectively. Furthermore, we demonstrated that the invasion-promoting effect of the tumor stroma cells was antagonized by TKI258 significantly. CCL5 stimulated invasion of MDA-MB-231 cells could be partially abrogated by TKI58 and/or by CCL5-neutralizing antibody. Therefore, it is most likely that the inhibitory effect of TKI258 on invasion of MDA-MB-231 cells in the presence of stroma cells is achieved, at least in part, by antagonizing the invasion-promoting effect of CCL5. Overall, our data show that TKI258 inhibited invasive capacities of aggressive breast cancer cell line MDA-MB-231, either in the absence or presence of tumor stroma cells in vitro. No significant financial relationships to disclose.