Abstract 5536: KB-164, a novel and highly potent Src family kinase inhibitor, reduces cancer cell invasion and abrogates downstream oncogenic pathways in triple negative breast cancer

Src is a non-receptor tyrosine kinase, which acts as an integrator of diverse signaling pathways used by cancer cells for cell proliferation, migration and metastasis. Recent interest in developing target specific therapy for improved benefits with manageable toxic effects has sharply increased the interest in testing new Src family kinase inhibitors for their potential anticancer therapeutic properties. In this study, we sought to investigate the chemical characteristics and the biological effects of the novel Src family kinase inhibitor KB-164, in Src expressing triple negative breast cancer cells. We show that KB-164 acts as a potent Src kinase inhibitor (IC50 1.3 nmol/L) in MDA-MB 231 cells, 100-fold more potent than the most widely used Src family kinase inhibitor dasatinib. At concentrations of 50nmol/L, KB-164 led to complete inhibition of Src activation for 48 hours. Analysis of downstream effectors of Src revealed that treatment with KB-164 inhibits the phosphorylation of several oncogenic pathways i.e. EGFR, ERK1/2, P38MAPK and AKT. A dramatic decrease in cancer cell motility and invasion was observed on treatment with KB-164 in both SUM 149 and MDA-MB 231 triple negative breast cancer cell lines. We also show that triple negative breast cancer cells derived from the patients are equally sensitive to growth inhibition by KB-164 within an IC50 of 1.8-nmol range. No cytotoxicity was observed both in vitro (18 micro mol/L in normal human mammary epithelial cells) and in vivo (70mg/kg in mice). Our findings indicate that KB-164 inhibits signaling pathways involved in controlling tumor cell proliferation and survival, suggesting that KB-164 might prove to be a promising therapeutic agent for breast cancer. Citation Format: Rabia A. Gilani, Kristoffer R. Brandvold, Li Wei Bao, Sameer Phadke, Michael E. Steffey, Matthew B. Soellner, Sofia D. Merajver. KB-164, a novel and highly potent Src family kinase inhibitor, reduces cancer cell invasion and abrogates downstream oncogenic pathways in triple negative breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5536. doi:10.1158/1538-7445.AM2015-5536