Abstract B109: Uncovering novel vulnerabilities in ovarian cancer by studying cell death in neoplastic transformation

Abstract High-grade serous ovarian carcinoma (HGSOC) is typically diagnosed at an advanced stage (III or IV) when the cancer is no longer locally confined and average 5-year survival rates are below 30%. Despite frequently having favorable initial responses to therapy, approximately 80% of HGSOC patients experience tumor recurrence and develop chemoresistance. This highlights the urgent need to better understand the mechanisms that drive transformation and tumor cell survival in early and late stages of this disease. Altered expression of BCL-2 family proteins that control the intrinsic apoptosis pathway is a prominent mechanism by which pre-cancerous cells evade cell death and tumor cells develop therapy resistance. Therefore, we sought to elucidate how changes in apoptotic regulation may contribute to neoplastic transformation and chemoresistance in HGSOC in order to uncover potential opportunities for improving early detection and treatment strategies. Because HGSOC is thought to develop predominately from fallopian tube secretory epithelial cells (FTSECs), we used immortalized and tumorigenic FTSEC lines in addition to well-validated HGSOC cell lines to measure apoptotic sensitivity and survival dependencies at three stages of transformation. Based on BH3 profiling and flow cytometry-based cell death analysis, we found that FTSECs and HGSOC cells are highly dependent on the BCL-2 family pro-survival protein BCL-XL to resist initiation of apoptosis. This rendered them particularly sensitive to BCL-XL inhibitors, including the first-generation BH3 mimetic A1331852 as well as novel proteolysis-targeting chimeras (PROTACs) that degrade BCL-XL. We also found that transformation by activation of the c-Myc oncogene increases apoptotic sensitivity and chemosensitivity of FTSECs while activation of Ras has the opposite effect and contributes to chemoresistance. Transcriptional profiling of primary tissue revealed 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. Further, to gain insight into mechanisms that may alter apoptosis during tumorigenesis, we are investigating how ovulation-related exposures drive apoptotic dysregulation in the formation of HGSOC precursor lesions, as greater number of lifetime ovulatory cycles is a major risk factor associated with this disease. We are exposing 2D and 3D models of the fallopian tube epithelium to patient-derived follicular fluid, known to contain mutagenic and inflammatory mediators, as well as sex steroid hormones which are enriched in follicular fluid and have been shown to control expression of BCL-2 family proteins. Again, using BH3 profiling, flow cytometry-based cell death analysis, and gene and protein expression measurements, we will uncover how acute and chronic exposures alter the expression, function and interaction of BCL-2 family proteins and may predispose the putative cell of origin of HGSOC to neoplastic transformation. Citation Format: Lissah K. Johnson, Maryam Azimi, Xingping Qin, Cameron Fraser, Elizabeth Stover, Yang Yang, Daohong Zhou, Bo Rueda, Kristopher Sarosiek. Uncovering novel vulnerabilities in ovarian cancer by studying cell death in neoplastic transformation abstract. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84 (5 Suppl₂): Abstract nr B109.