High-grade serous ovarian cancer (HGSOC) is the most common histological subtype of ovarian cancer, and it represents one of the most lethal gynaecological malignancies. Current treatments mainly include primary debulking surgery following Platinum-based therapies even if neoadjuvant chemotherapy before surgery has become a valid option. Besides an initial good response, a higher percentage of HGSOC-bearing patients relapses, showing a platinum-resistance disease with dissemination in the peritoneum, the omentum and the organs located in the abdominal cavity. In this scenario, by using a multidisciplinary approach on HGSOC cells and primary tumors, we identified the Pin1-Notch3 axis as new potential biomarker predictive of Platinum-response, thus suggesting its targeting to counteract the potential therapeutic failure. Indeed, genetic Pin1 inhibition impinges on Notch3 protein stability and function, thus leading to a decreased HGSOC progression and metastatic spread, and finally resulting in Platinum re-sensitization both in vitro and in vivo. Our study could allow the potential early stratification of patients into Platinum-sensitive and -resistant cohorts before clinical recurrence, thus supporting clinicians in selecting the most effective frontline treatment, finally resulting in therapeutic benefits and increased survival.

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