Objective:

To identify strategies that pharmacologically induce a functional HRD-like state in homologous recombination-proficient (HRP) ovarian cancer to enhance sensitivity to PARP inhibitors.

Approach:

Key Findings:

• Proteasome inhibitors, particularly ixazomib citrate, consistently sensitized HRP ovarian cancer models to PARP inhibition.
• Ixazomib citrate disrupted RAD51 recruitment to DNA damage sites, inducing a functional HRD-like state.
• Combination therapy with ixazomib citrate and olaparib significantly suppressed tumor growth in xenograft models.
• Proteasome inhibition increased tumor-surface MHC class I expression and enhanced susceptibility to CD8+ T-cell-mediated killing.

Interpretation:

Limitations:

• Theimmune-relatedobservationsareprimarilybasedoninvitrococultureexperimentsandshouldbeconsideredexploratory,requiringfurthervalidation.

Conclusion:

The study provides preclinical support for proteasome inhibition as a strategy to enhance the efficacy of PARP inhibitors in HRP ovarian cancer.

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