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

Nur Aininie Yusoh, Liping Su, Suet Lin Chia, Xiaohe Tian, Haslina Ahmad, Martin Gill Orcid Logo

Molecular Oncology, Volume: 19, Issue: 11, Pages: 3387 - 3408

Swansea University Author: Martin Gill Orcid Logo

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DOI (Published version): 10.1002/1878-0261.70093

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-proficie...

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Published in: Molecular Oncology
ISSN: 1574-7891 1878-0261
Published: Wiley 2025
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa69853
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.
Keywords: aromatase inhibitor; drug combination; PARP inhibitor; TNBC
College: Faculty of Science and Engineering
Funders: National Natural Science Foundation of China (Grant Number: 32171361); Llywodraeth Cymru (Grant Number: 80761-SU-242); Geran Putra Inisiatif Siswazah (Grant Number: GP-IPS/2022/9737200)
Issue: 11
Start Page: 3387
End Page: 3408

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