Abstract 6161: Targeting endogenous and therapy-induced dependence on BCL-XL in high grade serous ovarian carcinoma

Abstract Though most patients diagnosed with high-grade serous ovarian carcinoma (HGSOC) have favorable initial responses to therapy, approximately 80% will experience tumor recurrence and develop chemoresistant disease. This highlights the urgent need for more effective therapeutic strategies and a better understanding of the mechanisms that drive therapy resistance. Altered expression of BCL-2 family proteins that control the intrinsic apoptosis pathway is a prominent mechanism by which tumor cells can develop therapy resistance. Therefore, we sought to elucidate how changes in apoptotic regulation may contribute to chemoresistance in HGSOC in order to uncover potential opportunities for improving treatment outcomes. We used well-established HGSOC cell lines and human primary tumors to measure sensitivity to inhibitors of pro-survival BCL-2 family proteins as single agents and in combination with the front-line ovarian cancer chemotherapy drugs carboplatin and paclitaxel. Based on BH3 profiling, flow cytometry-based cell death analysis and colony formation assays, we found that HGSOC cells are particularly sensitive to BCL-XL inhibitors including the first-generation BH3 mimetics ABT-263 and A1331852 as well as novel proteolysis-targeting chimeras (PROTACs) that degrade BCL-XL. Clinical use of first-generation BCL-XL inhibitors has been hampered by thrombocytopenia resulting from platelet dependence on BCL-XL for survival. PROTACs have been developed to avoid this toxicity by degrading BCL-XL using the VHL E3 ligase, which is expressed at very low levels in platelets. We tested BCL-XL targeting in vivo using HGSOC xenografts in immunocompromised mice and found these tumors to be highly sensitive to BCL-XL inhibitors as single agents and in combination with chemotherapeutic agents. BCL-XL inhibitors reduced xenograft tumor growth and prolonged overall mouse survival. Importantly, thrombocytopenia was observed with in vivo use of first-generation BCL-XL inhibitors but not with use of BCL-XL targeting PROTACs. Transcriptional profiling demonstrated that expression levels of pro-apoptotic BAX and BAK, which initiate apoptosis by causing mitochondrial outer membrane permeabilization, increase during ovarian tumorigenesis, as do levels of BCL-XL. These changes are consistent with the increased BCL-XL dependence evident in HGSOC cells. We also detected BCL-XL dependence in ovarian cancer tumorigenesis models utilizing human fallopian tube secretory epithelial cells, the putative cell of origin for HGSOC. Overall, we find that BCL-XL inhibitors, especially PROTACs, can safely enhance the chemosensitivity of HGSOC cells in vitro and in vivo and may therefore prevent tumor recurrence in women diagnosed with this disease. Citation Format: Lissah Johnson, Xingping Qin, Cameron Fraser, Elizabeth Stover, Yang Yang, Daohong Zhou, Bo Rueda, Kristopher Sarosiek. Targeting endogenous and therapy-induced dependence on BCL-XL in high grade serous ovarian carcinoma [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 6161.