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Background <p>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.</p> Methods <p>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. </p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月11日

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  • Maria Valeria Giuli,
  • Angelica Mancusi,
  • Bianca Natiello,
  • Samuele Di Cristofano,
  • Rebecca Reali,
  • Maria Gemma Pignataro,
  • Daniel D’Andrea,
  • Laura Di Magno,
  • Carmine Nicoletti,
  • Alessandra Giorgi,
  • Alberto Macone,
  • Serena Camerini,
  • Marialuisa Casella,
  • Giovanna Peruzzi,
  • Sabrina Zema,
  • Gianluca Canettieri,
  • Federica Tomao,
  • Innocenza Palaia,
  • Angelina Pernazza,
  • Alessandra Rustighi,
  • Rocco Palermo,
  • Domenico Raimondo,
  • Alessandra Monti,
  • Nunzianna Doti,
  • Giulia d’Amati,
  • Giannino Del Sal,
  • Isabella Screpanti,
  • Claudio Talora,
  • Diana Bellavia,
  • Saula Checquolo

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.