Abstract 3113: Chronic type 1 interferon exposure phenocopies chronic cisplatin exposure in high grade serous ovarian cancer

Abstract Despite initial response to platinum-based therapeutics, high grade serous ovarian carcinoma (HGSOC) remains one of the deadliest gynecologic malignancies, due to high molecular and genetic heterogeneity that contributes to acquired drug resistance mechanisms and rapid recurrence. Frontline treatment for the disease has remained largely unchanged for 30 years, with CA125 serving as the only established biomarker for the past 4 decades and PARP inhibitors representing one of the few available targeted therapies. There is an urgent need for improved understanding of factors that may predict therapy response and tumor aggression, thus contributing to recurrence and resistance. We previously published on the dissociation of stemness and therapy resistance in an isogenic pair of therapy sensitive and resistant patient-derived HGSOC cells. RNA sequencing revealed enrichment of JAK/STAT signaling and an upregulation of gene signatures associated with type 1 interferon production and signaling in the chemo-resistant (CR) cells. We hypothesize that chronic, low-level IFN-1 signaling promotes the development of therapy resistance in HGSOC, via the priming of a DNA damage associated IFN-1 response. RT-qPCR and flow cytometry were used to validate the pathways and targets of interest. IFN-1 and pro-tumor interferon-related DNA damage signature (IRDS) genes were found to be significantly upregulated in the CR cells. Acute cisplatin treatment enriched IFN-1-related protein expression in all cells. CR and SE cells exhibited different temporal expression patterns of IFN-1 and IRDS RNA in response to acute cisplatin exposure, with SE cells displaying an acute IFN-1 response to cisplatin and CR cells responding with delayed IFN-1 induction. To determine if IFN-β is a driving factor in the development of resistance, cells were treated with chronic, low-level IFN-β for several weeks. Chronic, low-level IFN-β did not induce anti-viral ISG expression when compared to high dose cytokine after 24 hours. However, after 6 passages the treatment blunted ISG expression in both CR and SE cells. IFN-β treatment phenocopied several aspects of chronic cisplatin exposure: increased resistance to cisplatin, epithelial-like morphology changes, and reduced proliferation. Despite these changes, IFN response was dampened. Future studies aim to explore strategies for surmounting chemotherapy resistance by impacting IFN-I signaling. Citation Format: Ashlyn Conant, Kiera McGivney, Tise Suzuki, Sharon Asariah, Brigitte Vazquez, Jay Deng, HyeonJoo Cheon, Juli Unternaehrer. Chronic type 1 interferon exposure phenocopies chronic cisplatin exposure in high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3113.