RAD51 recruitment but not replication fork stability associates with PARP inhibitor response in ovarian cancer...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are a key treatment for BRCA1/2 mutant cancers.
• PARPi sensitivity is often linked to homologous recombination (HR) defects, but other HR factor roles, like replication fork protection, are also implicated.
• Understanding these mechanisms is crucial for expanding PARPi efficacy.

Purpose of the Study:

• To investigate PARPi sensitivity in ovarian cancer patient-derived xenograft (PDX) models.
• To correlate PARPi response with HR proficiency and replication fork protection.
• To identify novel mechanisms of PARPi sensitivity in BRCA1/2 wild-type cancers.

Main Methods:

• Analysis of BRCA1/2 status and genomic instability in 31 ovarian cancer PDX models.
• In vivo assessment of olaparib response in 15 selected PDX models.
• Ex vivo functional assessment of HR using irradiation-induced RAD51 foci formation and replication fork protection assays.
• Targeted panel sequencing of olaparib-sensitive models lacking BRCA1/2 alterations.

Main Results:

• 22.6% of PDX models harbored BRCA1/2 alterations, and 48.3% showed genomic instability.
• Ex vivo RAD51 foci formation successfully identified all in vivo olaparib-sensitive PDX models, including four without BRCA1/2 alterations.
• Replication fork protection and speed did not correlate with olaparib response.
• A MUS81 variant was identified as a potential mechanism for PARPi sensitivity in BRCA1/2 wild-type models.

Conclusions:

• Ex vivo RAD51 analysis is an effective predictor of in vivo olaparib response in ovarian cancer PDX models.
• A subset of PARPi-sensitive, HR-deficient ovarian cancer PDX models lacking BRCA1/2 alterations was identified.
• These findings suggest potential new therapeutic strategies for ovarian cancers with specific HR defects.