Multi-Omics Analysis Reveals the Attenuation of the Interferon Pathway as a Driver of Chemo-Refractory Ovarian Cancer

Afenteva, D.; Yu, R.; Rajavuori, A.; Salvadores, M.; Launonen, I.-M.; Lavikka, K.; Zhang, K.; Marchi, G.; Jamalzadeh, S.; Isoviita, V.-M.; Li, Y.; Micoli, G.; Erkan, E. P.; Falco, M. M.; Ungureanu, D.; Lahtinen, A.; Oikkonen, J.; Hietanen, S.; Vaharautio, A.; Sur, I.; Virtanen, A.; Farkkila, A.; Hynninen, J.; Muranen, T. A.; Taipale, J.; Hautaniemi, S.

doi:10.1101/2024.03.28.587131

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bioRxiv · 10.1101/2024.03.28.587131

Multi-Omics Analysis Reveals the Attenuation of the Interferon Pathway as a Driver of Chemo-Refractory Ovarian Cancer

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Abstract

Ovarian high-grade serous carcinoma (HGSC) represents the deadliest gynecological malignancy, with 10-15% of patients exhibiting primary resistance to first-line chemotherapy. These primarily chemo-refractory patients have particularly poor survival outcomes, emphasizing the urgent need for developing predictive biomarkers and novel therapeutic approaches. Here, we show that interferon type I (IFN-I) pathway activity in cancer cells is a crucial determinant of chemotherapy response in HGSC. Through a comprehensive multi-omics analysis within the DECIDER observational trial (ClinicalTrials.gov identifier NCT04846933) cohort, we identified that chemo-refractory HGSC is characterized by diminished IFN-I and enhanced hypoxia pathway activities. Importantly, IFN-I pathway activity was independently prognostic for patient survival, highlighting its potential as a biomarker. Our results elucidate the heterogeneity of treatment response at the molecular level and suggest that augmentation of IFN-I response could enhance chemosensitivity in refractory cases. This study underscores the potential of the IFN-I pathway as a therapeutic target and advocates for the initiation of clinical trials testing external modulators of the IFN-I response, promising a significant stride forward in the treatment of refractory HGSC.

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Afenteva, D., Yu, R., Rajavuori, A., Salvadores, M., Launonen, I.-M., Lavikka, K., Zhang, K., Marchi, G., Jamalzadeh, S., Isoviita, V.-M., Li, Y., Micoli, G., Erkan, E. P., Falco, M. M., Ungureanu, D., Lahtinen, A., Oikkonen, J., Hietanen, S., Vaharautio, A., Sur, I., Virtanen, A., Farkkila, A., Hynninen, J., Muranen, T. A., Taipale, J., Hautaniemi, S.. 2024-03-30. Multi-Omics Analysis Reveals the Attenuation of the Interferon Pathway as a Driver of Chemo-Refractory Ovarian Cancer. https://doi.org/10.1101/2024.03.28.587131

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