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

## TL;DR

A drug screen finds that combining Exemestane with Olaparib improves treatment for a hard-to-treat type of breast cancer.

## Contribution

Exemestane's ability to induce replication stress in BRCA-proficient TNBC is newly identified as a synergistic mechanism with PARP inhibitors.

## Key findings

- Exemestane synergizes with Olaparib to reduce tumor cell survival and increase DNA damage.
- Exemestane induces replication stress via ROS generation in BRCA-proficient TNBC cells.
- The drug combination shows enhanced tumor growth inhibition in a mouse model.

## Abstract

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.

Screening 166 FDA‐approved anticancer drugs identifies the aromatase inhibitor Exemestane as a synergistic partner of PARP inhibitor Olaparib in BRCA‐proficient triple‐negative breast cancer. Exemestane induces ROS‐mediated replication stress, enhancing DNA damage and apoptosis alongside Olaparib. This previously unreported effect suggests Exemestane could extend the use of PARP inhibitors to BRCA‐proficient TNBC, addressing a critical gap in current treatment options.