Abstract 364: Oxaliplatin and 5-fluorouracil cause therapy-induced senescence in low-grade serous ovarian cancer cells

Abstract A critical concern with managing low-grade serous ovarian cancer (LGSOC) is the lack of response to standard carboplatin-paclitaxel chemotherapy; less than 30% of patients respond to such initial chemotherapy. Oxaliplatin (OXP) and 5-Fluorouracil (5-FU) combination treatment is a standard treatment regimen against colorectal cancer (CRC); however, it could be repurposed for use against LGSOC. p53 wildtype CRC tumours have been shown to respond better to OXP & 5-FU suggesting that LGSOC, which is well-characterized to also be p53 wildtype, would also respond effectively to this treatment. Consequently, in this study, we utilized three LGSOC cell lines: VOA6406, VOA7681, and VOA1056. We determined the cytotoxic effects of treatment with OXP & 5-FU; viability, proliferation, clonogenic capacity, and drug-withdrawal recovery were assessed. Results showed a dramatic decrease in cell proliferation in the short-and-long term, without a reduction in cell viability. This effect was confirmed further by measuring Ki67, a marker of cell proliferation; OXP & 5-FU-treated cells showed a significant reduction in Ki67 labelling. The persistence in viability alongside the reduced cell proliferation in cells treated with OXP & 5-FU led us to hypothesize that this drug combination induces senescence in LGSOC cells. A critical aspect of senescence is the arrest of the cell cycle. A propidium iodide-based cell cycle assay, along with western blotting to measure expression of p53, p21, and pRb, demonstrated that the LGSOC cells treated with OXP & 5-FU were arresting at the G1-S phase. Morphology alterations and lysosomal swelling were measured via expression of senescence-associated β-galactosidase (SA-β-gal); OXP & 5-FU-treated LGSOC cells demonstrated a marked increase in SA-β-gal as well as a distinct flattening of cell morphology. Consistent with hallmarks of senescence, anti-apoptotic proteins Bcl-2 and Mcl-1, were elevated upon treatment with OXP & 5-FU. A compelling increase in reactive oxygen species (ROS) production, as well as an elevated expression of caveolin-1, suggest a senescence-induction pathway dependent on oxidative stress. The use of a known ROS quencher, α-tocopherol, confirmed this pathway, as it partially rescued the senescence phenotype induced by OXP & 5-FU. The use of OXP & 5-FU to induce senescence in LGSOC shows promise as an alternate treatment option for this rare disease. We will further study if facilitating a “one-two punch theory” could be used against LGSOC, whereby OXP & 5-FU induces senescence, which could be subsequently “cleared” by a senolytic drug. Citation Format: Rewati Prakash, Alicia A. Goyeneche, Edith Zorychta, Shuk On Annie Leung, Lucy Gilbert, Carlos Telleria. Oxaliplatin and 5-fluorouracil cause therapy-induced senescence in low-grade serous ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 364.