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REVIEW ARTICLE

Targeting EZH2 to mitigate immune checkpoint resistance in ARID1A-deficient triple-negative breast cancer

Lauren Lukas1* ,  Hye Ri Han1 ,  Evanthia T. Roussos Torres2 ,  Aaron G. Baugh2 ,  Oliver Bell3 ,  Jason C. Ye1 ,  Kenneth Wong1 ,  Vyshnavi Pachipulusu4 ,  Hualin Zhang1 ,  Alan L. Epstein4
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1 Department of Radiation Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
2 Department of Medicine, Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
3 Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
4 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
ARNM, 5132 https://doi.org/10.36922/arnm.5132
Submitted: 13 October 2024 | Revised: 24 December 2024 | Accepted: 25 December 2024 | Published: 16 January 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Immune checkpoint inhibitors (ICIs) have shown promise in treating triple-negative breast cancer (TNBC), but resistance to these therapies remains a significant challenge. AT-rich interactive domain 1A (ARID1A), a component of the SWItch/Sucrose Non-Fermentable chromatin remodeling complex, is frequently mutated in TNBC and is associated with increased programmed cell death ligand 1 expression, which contributes to immune evasion. Paradoxically, this mutation may make TNBC potentially more responsive to ICIs. Chromatin-mediated gene expression requires a balance between ARID1A and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, and ARID1A deficiency results in enhanced EZH2 activity, contributing to various oncologic processes. Epigenetic modulation through EZH2 inhibition could exploit the synthetic lethality between ARID1A deficiency and EZH2 activity, which may reduce the immunosuppressive tumor microenvironment and enhance infiltration and activity of cytotoxic T-cells within the tumor, thereby synergizing with immune checkpoint inhibition. This review explores the potential of EZH2 inhibition as a therapeutic strategy to overcome immune checkpoint resistance in ARID1A-deficient TNBC. In addition, the role of ARID1A deficiency as a radiosensitizer is also discussed in the context of combination therapy strategies.

Keywords
Epigenetic
Immunotherapy
Triple-negative breast cancer
Combination therapy
Radiotherapy
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
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Advances in Radiotherapy & Nuclear Medicine, Electronic ISSN: 2972-4392 Published by AccScience Publishing
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