High-grade serous ovarian cancer (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that primary HGSOC cultures undergo therapy-induced senescence (TIS) in response to DNA damage induced by chemotherapy. HGSOC-TIS displays most senescence hallmarks including persistent DNA damage, senescence-associated inflammatory secretome, and selective sensitivity to senolytic Bcl-2 family inhibitors, suggesting avenues for preferential synergistic clearance of these cells. Comparison of pre-and post-chemotherapy HGSOC patient tissue samples revealed changes in senescence biomarkers suggestive of post-treatment "in patient" TIS, and a stronger TIS response in post-chemotherapy tissues correlated with better 5-year survival rates for patients. Together, these data suggest that the induction of cellular senescence in HGSOC cells accounts at least in part for beneficial cellular responses to treatment in patients providing a new therapeutic target. (148/150 words) One Sentence Summary: Cellular senescence is a central beneficial response to chemotherapy in high-grade serous ovarian cancer both in vitro and in patient. Calvo et al. / 2018 3/36

High-grade serous ovarian carcinoma (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding the cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here, we find that more than 90% of tissue-derived primary HGSOC cultures, reflecting the original disease, retain the capacity to undergo stress-induced cellular senescence and primarily undergo therapy-induced senescence (TIS) in response to first-line carboplatin/taxol chemotherapy. HGSOC-TIS displays senescence-associated hallmarks, including a stable proliferation arrest, increased p16INK4A expression, persistent DNA damage, an inflammatory secretome, and senolytic sensitivity, suggesting new avenues for selective pharmacological manipulation of these cells. Comparison of pre- and post-chemotherapy patient HGSOC tissue samples revealed changes in physio-pathological senescence biomarkers supporting the occurrence of post-treatment TIS. Whether cell senescence induced by cancer therapy is beneficial or detrimental to treatment outcomes remains unknown. We find that patients with stronger TIS biomarkers in post-chemotherapy tissues have a more favorale 5-year survival, suggesting that the induction of senescence in HGSOC cells accounts, at least in part, for beneficial responses to treatment. Given that HGSOC cells almost universally retain the capacity to undergo senescence and that senescence appears beneficial in this context, senescence-centric therapeutic avenues should be further explored. Citation Format: Michael Skulimowski, Llilians Calvo-Gonzales, Shuofei Cheng, Isabelle Clément, Lise Portelance, Yu Zhan, Euridice Carmona, Manon de Ladurantaye, Julie Lafontaine, Kurosh Rahimi, Diane Provencher, Anne-Marie Mes-Masson, Francis Rodier. Senescence is a central response to chemotherapy in ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5833.

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