Interferon Beta Drives Therapy Resistance in a Patient Derived Model of High Grade Serous Ovarian Cancer

Conant, A.; Suzuki, T.; McGivney, K.; Ayyadevara, V. S. S. A.; Asariah, S.; Deng, J.; Nyein, E.; Coats, J.; Yu, G.; Ioffe, Y. J.; Hurtz, C.; Unternaehrer, J. J.

doi:10.64898/2026.01.27.699126

bioRxiv · 10.64898/2026.01.27.699126

Interferon Beta Drives Therapy Resistance in a Patient Derived Model of High Grade Serous Ovarian Cancer

Conant, A.·Suzuki, T.·McGivney, K.·Ayyadevara, V. S. S. A.·Asariah, S.·Deng, J.·Nyein, E.·Coats, J.·Yu, G.·Ioffe, Y. J.·Hurtz, C.·Unternaehrer, J. J.

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Abstract

Cancer cell-autonomous type 1 interferon (IFN-1) production and signaling is frequently activated in response to DNA damage and has been associated with the development of therapy resistance in several cancer types. However, its cell-autonomous role in driving resistance in high-grade serous ovarian cancer (HGSOC), a disease defined by near-universal exposure to genotoxic therapy as frontline treatment, remains unclear. Specifically, whether IFN-1 functions in HGSOC as only a response to genotoxic stress or can independently act in driving resistance phenotypes has not been studied. Utilizing a syngeneic 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 the interferon-related DNA damage resistance signature (IRDS). Acute cisplatin treatment elicited dynamic, temporal IFN-1 signaling and responses in both sensitive and resistant cells, indicating a conserved stress response in resistant cells. Chronic, low-level exposure to exogenous IFN{beta}, in the absence of a DNA-damaging agent, was sufficient to phenocopy several features of chronic cisplatin driven resistance, including reduced therapeutic sensitivity, cell cycle arrest, and decreased proliferation. Notably, IFN{beta} driven resistance occurred without sustained IRDS or canonical interferon stimulated gene (ISG) induction, revealing alternative mechanisms for IFN-1 mediated therapy resistance. Together, these findings identify IFN{beta} as a functional driver of the development of resistance-associated phenotypes and highlight cell-autonomous IFN-1 signaling as a potential biomarker for resistance and a therapeutic target in platinum-resistant disease.

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Conant, A., Suzuki, T., McGivney, K., Ayyadevara, V. S. S. A., Asariah, S., Deng, J., Nyein, E., Coats, J., Yu, G., Ioffe, Y. J., Hurtz, C., Unternaehrer, J. J.. 2026-01-28. Interferon Beta Drives Therapy Resistance in a Patient Derived Model of High Grade Serous Ovarian Cancer. https://doi.org/10.64898/2026.01.27.699126

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