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

TL;DR

This study shows that the Pin1/Notch3 pathway helps ovarian cancer cells resist platinum-based chemotherapy, and targeting Pin1 could improve treatment outcomes.

Contribution

The study identifies a novel functional circuit involving Pin1 and Notch3 that drives platinum resistance in ovarian cancer.

Findings

Carboplatin treatment activates the Pin1/Notch3 axis, promoting platinum resistance in HGSOC cells.

Genetic targeting of Pin1 sensitizes resistant cells to platinum therapy and reduces metastasis in preclinical models.

Pin1 stabilizes Notch3 by preventing its degradation, contributing to chemotherapy resistance.

Abstract

Resistance 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.

We 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.

Here, 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 GSK3β-mediated degradation, resulting in increased Notch3 expression.

Collectively, 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.

The online version contains supplementary material available at 10.1186/s13046-026-03658-x.

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