Abstract A35: Targeting Ras downstream to control motions: Rho GTPases

Ras activation is at the center of many signaling cascades that drive cell transformation and carcinogenesis. Strategies targeting inhibition of cellular functions of Ras can be multifaceted, from its upstream elements such as growth factors and integrin receptors to its remote downstream elements. Cell motility is one such major element that controls whether a cancer cell can be lethal to the human body. Without gaining cancer unique motile ability, a cancer cell's deadly impact of metastasis would be crippled and be eliminated through available anti-neoplastic approaches. There has been important progress in the discovery of small molecule modulators targeting the control machinery of cell motions, notably Rho subfamily of small GTPases, which is part of the Ras superfamily proteins. The classical proteins of the Rho GTPases are RhoA, Rac1, and Cdc42, which control the cytoplasmic tension (RhoA), cellular crawling (Rac1), and cellular scouting (Cdc42), respectively. Because these proteins are essential for cancer cell motility, establishment of a toolbox for the molecular modulators of their functions would significantly enhance the development of potential therapeutics aimed at targeting these pathways. Over the past decade, chemical compounds targeting RhoA pathway (Y-27632: Nature, 1997) and Rac1 (NSC23766: PNAS, 2004) became available. Our recent identification of a small molecule modulating Cdc42 (ZCL278: PNAS, 2013) has provided a complete reservoir that could be used to explore their differential effects on cancer cell behavior. ZCL278 and NSC23766 suppressed prostate cancer cell motility and they showed differential effects on cell survival. While ZCL278 did not decrease cell viability, NSC23766 did so in the same time frame. Our recent unpublished studies also found that they differentially influence cell cycle progression. Cells derived from different cancer types responded differently to Rac1 and Cdc42 modulation. Furthermore, cells derived from different individuals of the same cancer types responded differently, emphasizing the heterogeneity of potential drug responses of different cancers or same cancer types from different individuals. For example, in prostate cancer cells, ZCL278 increased S-phase block, resulting a diminished G2/M-phase in a dose-dependent manner whereas the effects of NSC23766 on G2/M reduction were not significant. In lung cancer cells, the effects of ZCL278 and NSC23776 on cell cycle were modified. NSC23766 did not in