Abstract 2617: Rac and Cdc42 inhibition on macrophage function in the pancreatic tumor microenvironment Free

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer. To date, there are few therapies that are efficient against this disease, and patients often develop therapy resistance. The homologous Rho GTPases, Rac and Cdc42, are overexpressed in pancreatic cancer and correlated with poor prognosis. Rho GTPases regulate cell migration/invasion, cell morphology/polarity, and cell survival/viability. Rac and Cdc42 are essential Rho GTPases in oncogenic transformation and invasiveness and govern invasion in both cancer cells and tumor-associated macrophages (TAMs). TAMs are immunosuppressive cells that exacerbate cancer progression via inflammatory responses and crosstalk signaling with malignant cancer cells to promote invasion and immunesuppression. Our laboratory has developed a dual Rac/Cdc42 inhibitor, MBQ-167 (IC₅₀ 100nM), as an anticancer agent that recently received IND approval from the US FDA due to its safety and efficacy in breast cancer models. The hypothesis tested in this study is that MBQ-167 will simultaneously target the migration and activity of pancreatic cancer cells and immunosuppressive cells in the tumor microenvironment (TME). To evaluate this, we performed pulldown assays for Rac and Cdc42 activation, MTT cell viability assays, wound-healing assays for cell migration, and phagocytosis assays using human and rat macrophage and human pancreatic cancer cell lines. Results show that MBQ-167 is not toxic to macrophages even at concentrations as high as 10uM. MBQ-167 inhibited Rac1activation by 75% and Cdc42 activation by 40% in THP-1 human macrophages at 500nM. MBQ-167 reduced macrophage migration by 67% at 150nM, and decreased pancreatic cancer cell migration by 60% at 250nM. In addition, MBQ-167 reduced macrophage phagocytosis by 56% at 500nM. This study demonstrates the utility of Rac/Cdc42 inhibition to reduce pancreatic cancer progression in the TME.

Citation Format: Anamaris Torres-Sánchez, Michael Rivera-Robles, Stephanie Dorta-Estremera, Suranganie Dharmawardhane. Rac and Cdc42 inhibition on macrophage function in the pancreatic tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2617.