Abstract C210: LIM kinase small molecule inhibitors block tumor cell invasion

The invasive potential of carcinomas greatly contributes to their ability to metastasize, a process which is estimated to cause 90% of all human cancer deaths. The LIM kinase (LIMK) family of Ser/Thr kinases sit at a hub of signaling pathways downstream of the Rho family of GTPases. Functionally, LIMK is directly involved in regulating the activity of cofilin, a family of proteins which modulate cell movement through reorganization of the actin cytoskeleton network. LIMK is up‐regulated in a number of invasive cancer cell lines and metastatic breast and prostate tumors, whilst an increase in LIMK activity has been shown to cause increased cellular invasion in multiple model systems. We demonstrate that LIMK inhibition by siRNA reduces the invasive capacity of MDA‐MB‐231‐Luc breast cancer cells in an in vitro matrigel invasion assay and reduces fibroblast lead collective invasion in a co‐culture organotypic model. Potent, selective, small molecule LIMK inhibitors have been identified that inhibit LIMK in vitro with sub‐nanomolar activity in biochemical assays and low micromolar activity in cells as measured by cofilin phosphorylation. Treatment of MDA‐MB‐231‐Luc cells or tumor associated fibroblasts with these small molecule inhibitors decreased cell invasion in vitro with minimal cellular toxicity. Collectively, these data further validate LIMK as an anti‐invasive therapeutic target in tumor cells and demonstrate the potential utility of LIMK inhibitors in metastatic disease. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C210.