Abstract 7061: Targeting metabolic vulnerabilities in ARID1A/B dual-deficient dedifferentiated endometrial carcinoma

Abstract Background: Dedifferentiated endometrial carcinoma (DDEC) is an aggressive endometrial carcinoma defined histologically by undifferentiated carcinoma juxtaposed against stage 1 or 2 endometrial adenocarcinoma. DDEC responds poorly to conventional platinum/taxane-based chemotherapy, particularly in the case of extrauterine spread. This highlights a need to develop novel therapies for individuals with DDEC. Genetically, a third of DDEC cases have co-inactivating mutations of ARID1A and ARID1B. These genes encode core subunits of the sucrose/switch non-fermentable (SWI/SNF) complex that regulate transcription. Furthermore, dual loss of ARID1A/B is believed to play a role in driving DDEC tumor development. We hypothesize that ARID1A/B dual-deficiency in DDEC generates unique genetic deficiencies that allow for the development of novel therapies for this cancer. We approached this hypothesis by first conducting a preliminary analysis of the Cancer Dependency Map (DepMap), which has identified vulnerabilities in mitochondrial functioning in ARID1A/B dual-deficient DDECs. As such, we aimed to understand the role of mitochondrial oxidative phosphorylation (OXPHOS) and redox homeostasis in ARID1A/B dual-deficient DDEC to create new treatment options. Methods: A panel of ARID1A/B dual-deficient and proficient endometrial cancer cell lines were treated with OXPHOS inhibitor IACS-010759 and reactive oxidative species (ROS) -inducing agent elesclomol to identify shifts in drug response between the two groups. To account for genomic differences between the cell lines, we also treated an ARID1B knock-out isogeneic cell line with the drugs. Additionally, changes in metabolism in the endometrial cancer cell lines were measured using Seahorse metabolic flux assays to determine if ARID1A/B dual-deficient cell lines have an increased dependency on OXPHOS for cell growth. Results: While the Seahorse assays revealed no significant difference in OXPHOS and glycolysis activities between the two groups, drug sensitivity assays demonstrated that ARID1A/B dual-deficient cancers are more sensitive to OXPHOS inhibition and increased ROS production than the proficient cell lines. Depletion of ARID1B in an ARID1A deficient cell line sensitizes the cells to both drugs. Furthermore, IACS-010759 significantly suppressed the growth of ARID1A/B-deficient DDEC xenograft tumor growth. Conclusion: ARID1A/B-dual deficient cancer cells rely on mitochondria function for survival. The underlying mechanisms are currently under investigation. Citation Format: Rebecca Ho, Eunice Li, Chae Young Shin, Shary Chen, David Huntsman, Yemin Wang. Targeting metabolic vulnerabilities in ARID1A/B dual-deficient dedifferentiated endometrial carcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7061.