ATF6-Mediated Signaling Contributes to PARP Inhibitor Resistance in Ovarian Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• High-grade serous ovarian cancer (HGSOC) presents a significant therapeutic challenge due to chemotherapy resistance.
• Poly (ADP-ribose) polymerase inhibitors (PARPi) are a targeted therapy, but resistance is a growing clinical problem.
• Overcoming PARPi resistance is crucial for improving disease-free survival in HGSOC patients.

Purpose of the Study:

• To identify mechanisms underlying PARPi resistance in HGSOC.
• To investigate the role of activating transcription factor 6 (ATF6) in mediating PARPi resistance.
• To explore the therapeutic potential of targeting the identified resistance pathway.

Main Methods:

• Establishment of isogeneic PARPi-sensitive and -resistant HGSOC cell lines.
• RNA sequencing and shRNA screening to identify key mediators of resistance.
• Analysis of publicly available HGSOC datasets and primary tumor cohorts.
• Inhibition of p38, a regulator of ATF6, in resistant cell lines and patient-derived xenograft (PDX) models.

Main Results:

• PARPi-resistant HGSOC models exhibited increased AP-1 transcriptional activity and DNA repair capacity.
• ATF6 was identified as a mediator of AP-1 activity, DNA damage response, and PARPi resistance.
• Elevated ATF6 expression in HGSOC correlates with poorer recurrence-free survival and clinical PARPi resistance.
• Inhibition of p38 in resistant models reduced AP-1 activity, DNA damage, tumor burden, and nuclear ATF6 accumulation.

Conclusions:

• A novel p38-ATF6-mediated AP-1 signaling axis contributes significantly to PARPi resistance in HGSOC.
• Targeting ATF6 or its regulators represents a promising strategy to overcome PARPi resistance.
• This study provides a clinical rationale for combining PARPi with AP-1 signaling inhibitors for HGSOC treatment.