Characterization of DNA damage repair pathway utilization in high-grade serous ovarian cancers yields rational...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Poly (ADP-ribose) polymerase inhibitors (PARPi) benefit ovarian high-grade serous carcinoma (HGSC) with homologous recombination deficiency (HRD).
• Homologous recombination proficient (HRP) HGSC tumors show resistance to PARPi, leading to poorer outcomes.
• PARPi toxicity necessitates combination therapies to reduce dosage and duration.

Purpose of the Study:

• To evaluate DNA double-strand damage repair pathways in HRD and HRP ovarian cancer cell lines.
• To investigate the efficacy of combining PARPi with ATM serine/threonine kinase inhibitors (ATMi) or ATR kinase inhibitors (ATRi).

Main Methods:

• Assessed DNA double-strand damage repair pathways in ovarian cancer cell lines with varying HR status.
• Treated cell lines with PARPi alone and in combination with ATMi or ATRi.
• Measured apoptosis, cell viability, colony formation, and NF-κB p65 phosphorylation.

Main Results:

• PARPi therapy reduced non-homologous end joining (NHEJ) in HRD cell lines.
• The combination of PARPi and ATMi synergistically increased apoptosis and decreased cell viability and colony formation in both HRD and HRP cells.
• PARPi plus ATMi decreased NF-κB p65 phosphorylation, unlike PARPi plus ATRi.

Conclusions:

• The combination of PARPi and ATMi represents a promising therapeutic strategy for HGSC, effective irrespective of the tumor's HR status.
• This combination may overcome resistance in HRP tumors and potentially allow for reduced PARPi toxicity.