Abstract A048: Promoting apoptotic cell death in mucinous ovarian cancer

Abstract Mucinous ovarian cancer (MOC) is a rare subtype of ovarian cancer that is relatively resistant to platinum and taxane chemotherapy and has poor prognosis in advanced stage and recurrent disease. Frequent genetic alterations in MOC include copy number alterations or mutations in CDKN2A/B, KRAS, and TP53, each present in over half of cases; ERBB2 (HER2) amplifications; and mutations in ARID1A, BRAF, and PIK3CA. We and others showed that high-grade serous and clear cell ovarian cancers are sensitive to the inhibition or degradation of BCL-XL, an anti-apoptotic protein in the intrinsic pathway of apoptosis, and that BCL-XL inhibitors can synergize with chemotherapy and targeted agents. Here we evaluated the intrinsic pathway of apoptosis in MOC cell lines and the efficacy of inhibitors of anti-apoptotic proteins combined with chemotherapy or targeted agents in MOC. Using 4 MOC cell lines (MCAS, RMUGS, JHOM1, COV644), we performed Western blots showing that MOC cell lines express anti-apoptotic proteins BCL-XL and MCL1 and multiple pro-apoptotic proteins in the intrinsic pathway of apoptosis. In analyses of genomic screening databases, some MOC cell lines show genetic dependency upon the genes encoding BCL-XL but not MCL1 or BCL-2. In our microscopy-based short-term cell viability assay, inhibitors of BCL-XL and BCL-2/BCL-XL produced some loss of viability in MOC cell lines, but MCL1 and BCL-2 inhibitors had minimal effects. A PROTAC degrader of BCL-XL, DT2216, also demonstrated activity against some MOC cell lines. Inhibitors of other cell death pathways were not effective, except for some activity seen with inhibitors of GPX4 (ferroptosis inducers). Combining BCL-XL inhibitor A1331852 with standard chemotherapeutics cisplatin, paclitaxel, 5-FU, or oxaliplatin demonstrated synergistic or additive effects in a subset of cell line/drug combinations but no effect in others. We are currently evaluating protein changes in MOC cell lines treated with chemotherapy and A1331852 using Western blot and reverse phase protein arrays to identify potential biomarkers and mechanisms of response. We also examined a panel of targeted drugs targeting pathways altered in MOC, including inhibitors of MEK/RAS/RAF, PI3K, HER2, VEGFR, SRC, and Wee1. Signals of activity were observed with MEK pathway inhibitors and Wee1 inhibitors across several MOC cell lines, and HER2 inhibitors in a subset of lines. Wee1 inhibitor adavosertib was active at sub-micromolar concentrations in each of the MOC cell lines tested. We are currently investigating mechanisms of adavosertib sensitivity, perhaps involving replication stress due to p53 mutations and oncogene activation, and combinations of adavosertib with BCL-XL inhibition. In summary, our data suggests that MOC may be dependent upon anti-apoptotic protein BCL-XL and BCL-XL inhibition may sensitize MOC to chemotherapy or targeted agents in selected instances. Wee1 inhibitor adavosertib shows preliminary efficacy in MOC with potential for clinical translation. Citation Format: Brendan Shay, Elizabeth Stover. Promoting apoptotic cell death in mucinous ovarian cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl): Abstract nr A048.