Olaparib delays resolution of IRE-induced DNA damage and enhances short-term antitumor activity in prostate cancer models

Objective: Residual cancer after irreversible electroporation (IRE) is usually discussed in relation to treatment margins and field coverage. We asked whether surviving prostate cancer cells also pass through a time-limited damage-recovery sequence that can be targeted with olaparib. Methods: We analyzed complementary transcriptomic datasets from distinct systems: single-cell RNA sequencing of RM1-luc tumors in C57BL/6 mice and bulk RNA sequencing of 22Rv1 cells after IRE. DNA damage, cell viability, colony formation, apoptosis and Ser139-phosphorylated histone H2AX (γH2AX) were examined in 22Rv1 and PC3 cells. The effect of adding olaparib after IRE was then tested in BALB/c nude mice bearing 22Rv1-luc xenografts. Results: , IRE plus olaparib resulted in lower tumor volume, tumor weight and bioluminescent signal than either treatment alone, with no marked body-weight loss during the short observation period. Conclusions: IRE induced a transient repair-associated vulnerability in prostate cancer models. Olaparib delayed the resolution of this damage and enhanced short-term antitumor activity following IRE, suggesting a repair-targeted sensitization strategy that merits further study.