Abstract B12: DOCK1 as a novel target for controlling RAS-driven cancer cell survival and invasion

Abstract

Abstract Oncogenic RAS contributes to malignant phenotypes of cancer cells by stimulating macropinocytosis-dependent nutrient uptake and promoting invasive migration. Because these cellular activities require remodeling of the actin cytoskeleton, which is regulated by the Rho family GTPase Rac, we hypothesized that molecules involved in Rac activation downstream of oncogenic RAS may be valuable targets for cancer therapy. DOCK1 is a Rac-specific guanine nucleotide exchange factor (GEF) implicated in malignancy of breast cancers and glioma. We show that genetic inactivation of endogenous DOCK1 in various RAS-transformed cells markedly suppressed their matrix invasion, macropinocytosis, and survival under glutamine-deprived conditions. We developed a selective inhibitor of DOCK1 that binds to the catalytic domain of DOCK1 and blocks its GEF activity. This inhibitor 1-(2-(3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)-5-pyrrolidinylsulfonyl-2(1H)-pyridone (TBOPP) blocked DOCK1-mediated invasion and macropinocytosis without impairing the immune-regulatory functions of its closely related protein DOCK2. Furthermore, TBOPP treatment suppressed cancer metastasis and growth in vivo in mice. To further assess the role of DOCK1 in RAS-driven cancers, we established the KPC mouse pancreatic ductal adenocarcinoma model bearing DOCK1 conditional knockout allele. Our results demonstrate that targeting DOCK1 could be an effective approach to treat RAS-driven cancers. Citation Format: Takehito Uruno, Yoshinori Fukui. DOCK1 as a novel target for controlling RAS-driven cancer cell survival and invasion [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B12.