PARP inhibition enhances exemestane efficacy in triple-negative breast cancer

Abstract

ABSTRACTTriple negative breast cancer (TNBC) remains the breast cancer subtype with the poorest prognosis and median survival rate. Targeting PARP1/2 with PARP inhibitors (PARPi) and achieving synthetic lethality is an effective strategy for TNBCs with BRCA1/2 mutations, however, the majority of TNBCs are BRCA1/2 wild type. Synergistic drug combinations with PARPi offers the potential to expand the use of PARPi towards BRCA-proficient cancers, including TNBC. To identify new PARPi combinations, we screened a library of 166 FDA-approved oncology drugs for synergy with the PARPi Olaparib in TNBC cells. We found that Exemestane, an aromatase inhibitor, synergised with Olaparib with a significant decrease in IC50values and clonogenicity accompanied by elevated DNA damage and apoptosis seen in combination treatment. The mechanistic basis for synergy was rationalised by the previously unreported ability of Exemestane to induce replication stress, as evidenced by ATR pathway activation and RPA foci formation. Low impact of this combination towards normal breast epithelial cells was observed and Exemestane has no reported severe toxicity as a monotherapy. This combination was able to achieve enhanced tumor growth inhibition in a murine xenograft model, greater than either drug employed as a single-agent. GO and KEGG enrichment analysis of differential genes indicated alterations in pathways associated with cell death in response to Exemestane and Olaparib treatment.