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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
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URI: https://cronfa.swan.ac.uk/Record/cronfa69853
first_indexed 2025-06-30T13:26:21Z
last_indexed 2025-11-14T12:40:54Z
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spelling 2025-11-13T12:29:11.6124188 v2 69853 2025-06-30 Olaparib synergy screen reveals Exemestane induces replication stress in triple‐negative breast cancer 485d85b532851e8863cd19c6af7e00f7 0000-0002-1371-5676 Martin Gill Martin Gill true false 2025-06-30 EAAS 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. Journal Article Molecular Oncology 19 11 3387 3408 Wiley 1574-7891 1878-0261 aromatase inhibitor; drug combination; PARP inhibitor; TNBC 13 7 2025 2025-07-13 10.1002/1878-0261.70093 COLLEGE NANME Engineering and Applied Sciences School COLLEGE CODE EAAS Swansea University SU Library paid the OA fee (TA Institutional Deal) 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) 2025-11-13T12:29:11.6124188 2025-06-30T14:21:56.3943085 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Nur Aininie Yusoh 1 Liping Su 2 Suet Lin Chia 3 Xiaohe Tian 4 Haslina Ahmad 5 Martin Gill 0000-0002-1371-5676 6 69853__34762__ba889082382e49d9ac31db9209ed86f5.pdf 69853.VoR.pdf 2025-07-15T10:41:30.3766834 Output 7181162 application/pdf Version of Record true Copyright: 2025 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License. true eng http://creativecommons.org/licenses/by/4.0/
title Olaparib synergy screen reveals Exemestane induces replication stress in triple‐negative breast cancer
spellingShingle Olaparib synergy screen reveals Exemestane induces replication stress in triple‐negative breast cancer
Martin Gill
title_short Olaparib synergy screen reveals Exemestane induces replication stress in triple‐negative breast cancer
title_full Olaparib synergy screen reveals Exemestane induces replication stress in triple‐negative breast cancer
title_fullStr Olaparib synergy screen reveals Exemestane induces replication stress in triple‐negative breast cancer
title_full_unstemmed Olaparib synergy screen reveals Exemestane induces replication stress in triple‐negative breast cancer
title_sort Olaparib synergy screen reveals Exemestane induces replication stress in triple‐negative breast cancer
author_id_str_mv 485d85b532851e8863cd19c6af7e00f7
author_id_fullname_str_mv 485d85b532851e8863cd19c6af7e00f7_***_Martin Gill
author Martin Gill
author2 Nur Aininie Yusoh
Liping Su
Suet Lin Chia
Xiaohe Tian
Haslina Ahmad
Martin Gill
format Journal article
container_title Molecular Oncology
container_volume 19
container_issue 11
container_start_page 3387
publishDate 2025
institution Swansea University
issn 1574-7891
1878-0261
doi_str_mv 10.1002/1878-0261.70093
publisher Wiley
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 1
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description 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.
published_date 2025-07-13T12:32:54Z
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