Prolyl-isomerase Pin1 drives platinum resistance by regulating Notch3 stability and function in ovarian cancer

BackgroundResistance to platinum-based drugs represents a major obstacle for the management of high-grade serous ovarian cancer (HGSOC) patients. Indeed, the selective pressure of platinum-based (PT) chemotherapy often leads to the outgrowth of platinum-resistant subclones. In this scenario, the underlying adaptive networks should be fully investigated to provide advances toward more streamlined and personalized care.MethodsWe conducted a comprehensive analysis of Pin1/Notch3relationship from HGSOC cell lines and primary tumours, integrating multiple genetic targeting under chemotherapy pressure, differential proteomic approaches, molecular docking data and dynamics simulations, thus identifying a functional circuit evaluated in vitro and in vivo models.We conducted a comprehensive analysis of relationship from HGSOC cell lines and primary tumours, integrating multiple genetic targeting under chemotherapy pressure, differential proteomic approaches, molecular docking data and dynamics simulations, thus identifying a functional circuit evaluated in vitro and in vivo models.ResultsHere, we demonstrated that carboplatin treatment of HGSOC cells promoted the activation of the Pin1/Notch3 axis, resulting in platinum resistance. Accordingly, HGSOC-bearing patients showing increased Pin1/Notch3 co-expression after PT-based chemotherapy correlated with a clinical worse response. Conversely, genetic targeting of Pin1 combined with carboplatin treatment sensitizes resistant cells to platinum-based therapy, both in vitro and in vivo, strongly reducing their Notch3-mediated metastatic potential in preclinical murine models. Mechanistically, Pin1-Notch3 binding favours protection of Notch3 from its GSK3 beta-mediated degradation, resulting in increased Notch3 expression.ConclusionsCollectively, our findings identify the functional Pin1/Notch3 axis as an escape strategy from chemotherapy-induced cell death, thus suggesting a novel predictive role of the Pin1/Notch3 axis in the platinum response, which could be useful for implementing frontline treatments for HGSOC patients before recurrence.