Abstract 3707: UXS1 is a synthetic lethal target in cancer

Abstract

Abstract Studies presented here were conducted to validate UXS1 as a synthetic lethal target in UGDHhigh expressing cancer. In vitro and in vivo knockout studies were used to investigate the role of UXS1 in UGDH-high cancers. UXS1 has been validated as a synthetic lethal target in cancer cell lines highly expressing UGDH in vitro by CRISPR-mediated knockout of UXS1 in a panel of lung cancer cell lines. In addition to UGDH expression predicting UXS1 dependency, we have shown UGDH overexpression functional drives UXS1 dependency, such that knockout of UGDH rescues cellular growth defects seen with UXS1-knockout alone. Furthermore, catalytic activity of UXS1 was shown to be required, as wildtype but not catalytic deficient UXS1 was able to rescue cellular growth defects seen with endogenous UXS1 knockout in UGDH-high cancer cell lines. Together this data suggests that dysregulation of some metabolite(s) is driven by high expression of UGDH when knockout of UXS1 prevents normal pathway flux of UDP-Glucuronic Acid (UDP-GA) to be converted to UDP-Xylose (UDP-X), leading to the synthetic lethal effect observed as impaired cellular growth. To validate UXS1 as a target in vivo, an inducible genetic knockout system to knockout UXS1 showed impaired tumor growth, but no tumor regression. Sanger sequencing of UXS1 knockout efficiency at different time course suggested a slow and incomplete dropout of the UXS1-KO cells in vivo. Although in vitro efforts have shown UXS1 to a synthetic lethal target, the failure to induce a robust in vivo effect of UXS1 knockout have casted doubts on the promise of UXS1 being an effective target for the proposed indication. Citation Format: Michelle Patricia Cicchini, Shuzhen Wu, Yang Peng, Yanhua Rao. UXS1 is a synthetic lethal target in cancer. [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 3707.