Abstract #1091: TKI258, a novel, multi-targeted tyrosine kinase inhibitor for the treatment of breast cancer
Authors: Hongyu Liu, Annette Dieing, Sylvia Lehenbauer-Dehm, Dagmar Kühnhardt, Anne Regierer, Carsten Schulz, Benjamin Storek, Sandra Schwarck, Kurt Possinger, Jan Eucker
Journal: Cancer Research (2009)

TKI258 (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 etc. 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. Triple-negative (ER, PR and Her-2 negative) breast cancer is a small subtype of breast cancer which accounts for about 15% of all breast cancer patients. These tumors are currently managed only with standard treatment. Clinically validated molecular targeted therapies are still missing. The outcome for this type of breast cancer is very poor due to high rate of local and systemic relapse. In this study, we chose the highly invasive triple-negative breast cancer cell line MDA-MB-231, 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 through the matrigel-coated transwell membrane in a dose-dependent manner. In association with this effect, TKI258 down-regulated the phosphorylation of ERK1/2 and STAT3 and inhibited the VEGF production in the cell supernatants. Most interestingly, by co-culture of MDA-MB-231 cells with breast cancer stroma cells or with human mesenchymal stem cells we demonstrated that the invasion-promoting effect of the tumor stroma cells or mesenchymal stem cells was antagonized by TKI258 dramatically. It has been indicated that CCL5 (Rantes) and CCL2 (MCP-1), two inflammatory chemokines, are crucial factors to mediate tumor-stroma interaction leading to enhanced invasion of many malignant cells, including breast cancer. 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. This data correlated with the produced chemokines in cell culture media by MDA-MB-231 alone, stroma cells alone, or MDA-MB-231/stroma co-culture as measured by ELISA. Furthermore, CCL5/CCL2 stimulated invasion of MDA-MB-231 cells could be partially abrogated by CCL5/CCL2-neutralizing antibody. Therefore, 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/CCL2. Overall, our data show that TKI258 inhibited invasive capacities of triple-negative breast cancer cell line MDA-MB-231, either in the absence or presence of tumor stroma cells in  vitro . This effect may possibly mediated by inhibiting the invasion-promoting effects of certain inflammatory chemokines/cytokines which are secreted by tumor and/or stroma cells.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1091.