LAUSR

The RhoGTPases Rac and Cdc42 are excellent therapeutic targets for inhibiting metastasis because these homologous proteins regulate numerous cellular functions that promote tumorigenesis, angiogenesis, invasion and therefore, metastasis. Also, Rac1, Cdc42, and their effector p21-activated kinase (PAK) are overexpressed in multiple cancer types, including breast, gastric, and pancreatic, and are associated with higher mortality rates. Furthermore, Rac and Cdc42 are activated through the signaling of oncogenic cell surface receptors such as EGFR and HER2, therefore hyperactivating their signaling pathways. Our laboratory has developed two small molecules targeting Rac and Cdc42, Ehop-016 and MBQ-167, that inhibit Rac1 and Cdc42 with IC 50 s in the low micro- and nano-molar concentrations, respectively (Montalvo-Ortiz et al. 2012, J Biol Chem; Humphries-Bickley et al. 2017, Mol Cancer Therap), making them the most potent Rac/Cdc42 inhibitors developed to date. We hypothesize that targeting Rac1, 3, and Cdc42 is a rational strategy to inhibit aggressive TNBC, pancreatic and gastric cancer. To test this hypothesis, we treated the TNBC cell lines MDA-MB-231, MDA-MB-468 and 4T1 (murine breast cancer), gastric cancer cells NCI-N87, and pancreatic cancer cells MIA-PaCa-2 with 4uM and 500nM of Ehop-016 and MBQ-167 respectively, and measured cell viability. Both TNBC cell lines and the pancreatic cancer cell line exhibited a drastic reduction in cell viability (g 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2185.