PI: Piera Tocci
Other IRE Principal Collaborators: Bagnato Anna, Blandino Giovanni, Carosi Mariantonia, Sacconi Andrea, Savarese Antonella, Vizza Enrico, Caprara Valentina

Project Code: 28919

Project Duration: 60 months

This project aims to investigate the role of mechanical signaling mediated by the endothelin-1 (ET-1)/PIEZO1/YAP axis in promoting resistance to PARP inhibitors (PARPi) in high-grade serous ovarian cancer (HG-SOC). Despite PARPi’s efficacy, resistance remains a major clinical challenge. Emerging evidence suggests that mechanical cues from the tumor microenvironment, including extracellular matrix (ECM) stiffness and ET-1 signaling, activate YAP and downstream pathways, fostering DNA damage response (DDR) dysregulation and immune evasion. This study will explore how ET-1/PIEZO1/YAP-driven mechanotransduction influences PARPi resistance by modulating DDR (via ATR and POLθ) and pro-inflammatory signaling (via cGAS-STING). The project will employ patient-derived (PD) models, 3D cultures, and preclinical mouse models to evaluate novel combinatorial therapies targeting ET-1R (macitentan), DDR (ATRi, POLθi), and immune checkpoints (anti-PD-L1).

The primary goal is to dissect the molecular mechanisms by which mechanical forces and ET-1/PIEZO1/YAP signaling drive PARPi resistance in HG-SOC. By elucidating these pathways, the project seeks to:

• Define how ECM stiffness and ET-1 signaling converge on YAP to regulate DDR and immune evasion.
• Identify therapeutic synergies between macitentan, PARPi, DDR inhibitors, and immunotherapy to resensitize resistant tumors.
• Develop actionable strategies to overcome PARPi resistance by targeting mechanosensitive and immune-suppressive pathways.

Mechanistic Insights: Demonstration that ET-1/PIEZO1/YAP activation promotes PARPi resistance via ATR/POLθ-dependent DDR and cGAS-STING-mediated immune suppression.

Translational Outcomes: Validation of macitentan as a sensitizing agent for PARPi in combination with ATRi, POLθi, or immune checkpoint inhibitors (ICI) in PD models and PDX.

Therapeutic Advancements: Preclinical evidence supporting combinatorial regimens that disrupt mechanical signaling to restore PARPi efficacy and enhance immune surveillance.

This study will provide a foundation for clinical trials testing macitentan-based combinations in HG-SOC, addressing an unmet need in overcoming PARPi resistance through mechano-immunomodulation.