Olaparib synergy screen reveals Exemestane induces replication stress in triple‐negative breast cancer

Triple-negative breast cancer (TNBC) remains the breast cancer subtype with the poorest prognosis. While PARP inhibitors (PARPi) effectively target BRCA1/2-mutant TNBCs via synthetic lethality, most TNBCs are BRCA1/2 wild-type. Synergistic drug combinations may expand PARPi efficacy to BRCA-proficient TNBC. To identify new PARPi combinations, we screened a library of 166 FDA-approved oncology drugs for synergy with Olaparib in TNBC cells. We found that Exemestane, an aromatase inhibitor, synergized with Olaparib, significantly decreasing IC₅₀ values and clonogenicity while increasing DNA damage and apoptosis. The mechanistic basis for this synergy was rationalized by the previously unreported ability of Exemestane to induce replication stress via reactive oxygen species (ROS) generation and oxidative stress. This combination had low cytotoxicity toward normal breast epithelial cells, and Exemestane has no reported severe toxicity as a monotherapy. The combination of Olaparib and Exemestane was able to achieve enhanced tumor growth inhibition in a murine xenograft model, greater than either drug employed as a single agent, and GO and KEGG enrichment analysis indicated alterations in pathways associated with cell death in response to Exemestane and Olaparib treatment.