Abstract 927: Combined targeting c-Src and c-Met pathways to impair prostate cancer cell growth and invasion.

Abstract

Abstract Overexpression of tyrosine kinases c-Src and c-Met has been shown to be highly associated with prostate cancer progression and poor clinical outcomes, therefore small molecule Src or Met inhibitors are being extensively evaluated in clinical trials for advanced prostate cancer. However clinical data suggest that single treatment with any of these inhibitors only yield limited effects in patients. One possibility is that redundant signaling pathways in tumor cells exist that allows tumor cell uninterrupted upon blockade of purely one pathway. We hypothesize that c-Src and c-Met are two compensatory pathways that may cooperate to promote prostate cancer progression, hence here we studied treatment effects of combining inhibitors targeting c-Src (dasatinib, saracatinib) and c-Met (ASLAN002, also named BMS-777607) on multiple functional behaviors associated with tumor growth and metastasis in c-Src and c-Met expressing prostate cancer cells (PC-3, DU145). Combination of Src inhibitors and ASLAN002 was found to inhibit cell proliferation and colony formation more strongly than either single agent, as assessed by MTT and clonogenicity, respectively. In a wound-healing assay, compared to either treatment alone, the combinatorial treatment exhibited greater suppression on cell motility induced by hepatocyte growth factor, the only known ligand of c-Met. Similarly, using a Matrigel-based Transwell assay, Src inhibitors plus ASLAN002 resulted in significant reduction of cell invasion in the presence or absence of HGF. Western blot analysis demonstrated that co-targeting Met and Src kinases lead to not only inhibition on c-Met and c-Src autophosphorylation but also greater blockade of multiple downstream kinases such as focal adhesion kinase (FAK), Akt and extracellular signal-regulated kinase (ERK). These data indicate that combined application of small molecule Src and Met inhibitors cause significant impairment on various phenotypes associated with prostate cancer progression in vitro including proliferation, survival, migration and invasion, suggesting that this combination intervention modality may serve as a potential anti-metastatic strategy that could be further tested in metastatic prostate cancer models in vivo. Citation Format: Yao Dai, Kyung-Mi Bae, Dietmar W. Siemann. Combined targeting c-Src and c-Met pathways to impair prostate cancer cell growth and invasion. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 927. doi:10.1158/1538-7445.AM2013-927