ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27

Anti-HER2 antibodies are effective but often lead to resistance in patients with HER2+ breast cancer. Here, we report an epigenetic crosstalk with aberrant glycerophospholipid metabolism and inflammation as a key resistance mechanism of anti-HER2 therapies in HER2+ breast cancer. Histone reader ZMYN...

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Detalles Bibliográficos
Autores: Wang, Yong, Wang, Yanan, Bao, Lei, Vale, Goncalo, McDonald, Jeffrey G., Fang, Yisheng, Peng, Yan, Kumar, Ashwani, Xing, Chao, Brasó-Maristany, Fara, Prat Aparicio, Aleix, Arteaga, Carlos L., Wang, Yingfei, Luo, Weibo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universidad de Oviedo (UNIOVI)
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/227115
Acceso en línea:https://hdl.handle.net/2445/227115
Access Level:acceso abierto
Palabra clave:Càncer de mama
Oncologia
Epigenètica
Breast cancer
Oncology
Epigenetics
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spelling ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27Wang, YongWang, YananBao, LeiVale, GoncaloMcDonald, Jeffrey G.Fang, YishengPeng, YanKumar, AshwaniXing, ChaoBrasó-Maristany, FaraPrat Aparicio, AleixArteaga, Carlos L.Wang, YingfeiLuo, WeiboCàncer de mamaOncologiaEpigenèticaBreast cancerOncologyEpigeneticsAnti-HER2 antibodies are effective but often lead to resistance in patients with HER2+ breast cancer. Here, we report an epigenetic crosstalk with aberrant glycerophospholipid metabolism and inflammation as a key resistance mechanism of anti-HER2 therapies in HER2+ breast cancer. Histone reader ZMYND8 specifically confers resistance to cancer cells against trastuzumab and/or pertuzumab. Mechanistically, ZMYND8 enhances cPLA2α expression in resistant tumor cells through inducing c-Myc. cPLA2α inactivates phosphatidylcholine-specific phospholipase C to inhibit phosphatidylcholine breakdown into diacylglycerol, which diminishes protein kinase C activity leading to interleukin-27 secretion. Supplementation with interleukin-27 protein counteracts cPLA2α loss to reinforce trastuzumab resistance in HER2+ tumor cells and patient-derived organoids. Upregulation of ZMYND8, c-Myc, cPLA2α, and IL-27 is prevalent in HER2+ breast cancer patients following HER2-targeted therapies. Targeting c-Myc or cPLA2α effectively overcomes anti-HER2 therapy resistance in patient-derived xenografts. Collectively, this study uncovers a druggable signaling cascade that drives resistance to HER2-targeted therapies in HER2+ breast cancer.Nature Publishing Group2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/227115Articles publicats en revistes (Medicina)reponame:Dipòsit Digital de la UBinstname:Universidad de Oviedo (UNIOVI)InglésReproducció del document publicat a: https://doi.org/10.1038/s41467-025-59184-5Nature Communications, 2025, vol. 1, num.3908https://doi.org/10.1038/s41467-025-59184-5cc-by-nc-nd (c) Yong Wang et al., 2025https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2271152026-05-27T06:46:51Z
dc.title.none.fl_str_mv ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27
title ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27
spellingShingle ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27
Wang, Yong
Càncer de mama
Oncologia
Epigenètica
Breast cancer
Oncology
Epigenetics
title_short ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27
title_full ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27
title_fullStr ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27
title_full_unstemmed ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27
title_sort ZMYND8 drives HER2 antibody resistance in breast cancer via lipid control of IL-27
dc.creator.none.fl_str_mv Wang, Yong
Wang, Yanan
Bao, Lei
Vale, Goncalo
McDonald, Jeffrey G.
Fang, Yisheng
Peng, Yan
Kumar, Ashwani
Xing, Chao
Brasó-Maristany, Fara
Prat Aparicio, Aleix
Arteaga, Carlos L.
Wang, Yingfei
Luo, Weibo
author Wang, Yong
author_facet Wang, Yong
Wang, Yanan
Bao, Lei
Vale, Goncalo
McDonald, Jeffrey G.
Fang, Yisheng
Peng, Yan
Kumar, Ashwani
Xing, Chao
Brasó-Maristany, Fara
Prat Aparicio, Aleix
Arteaga, Carlos L.
Wang, Yingfei
Luo, Weibo
author_role author
author2 Wang, Yanan
Bao, Lei
Vale, Goncalo
McDonald, Jeffrey G.
Fang, Yisheng
Peng, Yan
Kumar, Ashwani
Xing, Chao
Brasó-Maristany, Fara
Prat Aparicio, Aleix
Arteaga, Carlos L.
Wang, Yingfei
Luo, Weibo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer de mama
Oncologia
Epigenètica
Breast cancer
Oncology
Epigenetics
topic Càncer de mama
Oncologia
Epigenètica
Breast cancer
Oncology
Epigenetics
description Anti-HER2 antibodies are effective but often lead to resistance in patients with HER2+ breast cancer. Here, we report an epigenetic crosstalk with aberrant glycerophospholipid metabolism and inflammation as a key resistance mechanism of anti-HER2 therapies in HER2+ breast cancer. Histone reader ZMYND8 specifically confers resistance to cancer cells against trastuzumab and/or pertuzumab. Mechanistically, ZMYND8 enhances cPLA2α expression in resistant tumor cells through inducing c-Myc. cPLA2α inactivates phosphatidylcholine-specific phospholipase C to inhibit phosphatidylcholine breakdown into diacylglycerol, which diminishes protein kinase C activity leading to interleukin-27 secretion. Supplementation with interleukin-27 protein counteracts cPLA2α loss to reinforce trastuzumab resistance in HER2+ tumor cells and patient-derived organoids. Upregulation of ZMYND8, c-Myc, cPLA2α, and IL-27 is prevalent in HER2+ breast cancer patients following HER2-targeted therapies. Targeting c-Myc or cPLA2α effectively overcomes anti-HER2 therapy resistance in patient-derived xenografts. Collectively, this study uncovers a druggable signaling cascade that drives resistance to HER2-targeted therapies in HER2+ breast cancer.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/227115
url https://hdl.handle.net/2445/227115
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/s41467-025-59184-5
Nature Communications, 2025, vol. 1, num.3908
https://doi.org/10.1038/s41467-025-59184-5
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Yong Wang et al., 2025
https://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Yong Wang et al., 2025
https://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Oviedo (UNIOVI)
instname_str Universidad de Oviedo (UNIOVI)
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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