Interferon beta drives therapy resistance in a patient-derived model of high-grade serous ovarian cancer.

Type 1 interferon (IFN-1) production and signaling are frequently activated in response to DNA damage and have been associated with the development of therapy resistance in cancer. However, the cell-autonomous role of IFN-1 in driving resistance in high-grade serous ovarian cancer (HGSOC) remains unclear. Specifically, whether IFN-1 functions in HGSOC as solely a response to genotoxic stress due to genotoxic therapy as frontline treatment, or can independently act in driving resistance phenotypes, has not been studied. Utilizing a patient-derived model of cisplatin-sensitive (SE) and -resistant (CR) HGSOC, we demonstrate that chronic cisplatin exposure is associated with enrichment of IFN-1 signaling and an interferon-related DNA damage resistance signature. Acute cisplatin treatment elicited dynamic IFN-1 signaling in both SE and CR cells, indicating a conserved stress response. However, chronic, low-level exposure to exogenous IFNβ, without a DNA-damaging agent, phenocopied several features of chronic cisplatin-driven resistance, including reduced therapeutic sensitivity and decreased proliferation. Together, these findings identify IFNβ as a driver of resistance-associated phenotypes and highlight cell-autonomous IFN-1 signaling as a potential biomarker for resistance and therapeutic target in platinum-resistant disease.