Abstract 1459: Selective killing of SMARCA4-deficient gynecologic cancers by mitochondria oxidative phosphorylation inhibitors

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) and dedifferentiated carcinoma of the ovary or endometrium are rare but highly aggressive types of gynecologic cancers. We and others have recently demonstrated that genetic inactivation of SMARCA4, one of the two ATPases of the SWI/SNF chromatin remodeling complex, along with protein loss is the only recurrent somatic mutation of SCCOHT. Furthermore, SMARCA4 loss appears as a key event in the development of a subset of dedifferentiated carcinoma of the ovary, endometrium or other organs. These SMARCA4-deficient dedifferentiated tumors and SCCOHT usually lose the expression of SMARCA2, the alternative ATPase of the SWI/SNF complex. Through mining the publicly available genome-wide CRISPR screen database from the Broad Institute DepMap Project for about 500 cell lines, we identified that SMARCA4/A2-dual deficient ovarian cell lines are selectively sensitive to the genetic ablation of multiple components of mitochondria electron transfer chain (ETC). Using seahorse metabolism assays, we revealed that SCCOHT cells have reduced glycolysis in comparison to other ovarian cancer cells and utilize mitochondria respiration for energy production regardless of the availability of glucose. Accordingly, both SCCOHT and SMARCA4-deficient dedifferentiated ovarian carcinoma cell lines are remarkably more sensitive to several inhibitors of ETC complex I, and tigecycline, a selective inhibitor of the mitochondria ribosomal translation, than other ovarian cancer cells, such as SMARCA4-intact ovarian high-grade serous carcinoma cells and clear cell ovarian carcinoma cells regardless of the expression level of ARID1A, a SWI/SNF complex subunit frequently lost in clear cell ovarian carcinoma. Re-expression of SMARCA4 increased the expression of SLC2A1, encoding the glucose transporter GLUT1, and decreased the sensitivity of SCCOHT cells to ETC complex I inhibitors, suggesting that SMARCA4 loss may reduce the transport of glucose leading to reduced glycolysis and increased reliance on mitochondria respiration, which is currently under investigation. Therefore, our data suggest that selective targeting mitochondria respiratory complex function can be an effective strategy for SCCOHT and other SMARCA4-deficient dedifferentiated cancers of gynecologic tract or other organs. Citation Format: Yemin Wang, Dionzie Ong, Shary Yuting Chen, Eunice Li, Krystal Orlando, Elizabeth Raupach, Jennifer Ji, Bernard Weissman, Patrick Pirrotte, David Humtsman. Selective killing of SMARCA4-deficient gynecologic cancers by mitochondria oxidative phosphorylation inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1459.