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HER3-DXd (patritumab deruxtecan) is currently under clinical investigation for HER3-expressing metastatic BC. However, strategies to further enhance its efficacy, particularly in endocrine therapy\u2013resistant settings, are urgently needed. We hypothesised that targeting ATR, a key regulator of DNA damage repair (DDR), potentiates HER3-DXd in HER3+\/HR+\u2009BC, including tamoxifen\u2013resistant (TMR) disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Synergistic partners for HER3-DXd were identified by whole-genome RNAi screening. Treatments\u2019 effects on cell cycle, DNA damage, and protein expression were analysed using flow cytometry, comet assay, and Western blotting, respectively. Treatments\u2019 antitumor efficacy was assessed using xenograft mouse models. TCGA and CPTAC databases were analysed for clinical relevance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HER3-DXd inhibited growth in both parental and TMR MCF7 and T47D cells. Compared to monotherapies, combining HER3-DXd with an ATR inhibitor enhanced DNA damage, sub-G1 arrest, apoptosis, downregulation of DDR and cell cycle regulatory proteins, and tumour growth inhibition. TCGA and CPTAC analyses confirmed high HER3 expression and correlation of\n                      <jats:italic>ATR<\/jats:italic>\n                      ,\n                      <jats:italic>CHEK1<\/jats:italic>\n                      , and\n                      <jats:italic>TOP1<\/jats:italic>\n                      gene expression with poor prognosis in HR+\u2009BC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Combining HER3-DXd with an ATR inhibitor could benefit HER3+\/HR+\u2009BC patients with both endocrine\u2013sensitive and \u2013resistant diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41416-026-03413-1","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T05:03:16Z","timestamp":1776229396000},"page":"33-47","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ATR inhibition potentiates the antitumor efficacy of HER3-DXd in HER3-positive\/HR-positive breast cancer by increasing DNA damage"],"prefix":"10.1038","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0409-2294","authenticated-orcid":false,"given":"Xuemei","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6862-5686","authenticated-orcid":false,"given":"Jangsoon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Jin","family":"Gi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanasis","family":"Poullikkas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon A.","family":"Fuson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pang-Dian","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jami A.","family":"Fukui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5711-2404","authenticated-orcid":false,"given":"Debu","family":"Tripathy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0166-7275","authenticated-orcid":false,"given":"Naoto T.","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"3413_CR1","doi-asserted-by":"publisher","first-page":"283","DOI":"10.3389\/fphar.2015.00283","volume":"6","author":"A Appert-Collin","year":"2015","unstructured":"Appert-Collin A, Hubert P, Cremel G, Bennasroune A. 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Ueno reports consulting roles for AstraZeneca Pharmaceuticals LP (USA and UK), Bayer AG, Bristol Myers Squibb Company, Carna Biosciences Inc., CytoDyn Inc., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly, Genentech Inc., Genomic Health Inc., Gilead Sciences Inc., Lavender Health, OncoCyte Corporation, Pear Bio, Peptilogics Inc., Pfizer Inc., Phoenix Molecular Designs, Preferred Medicine, Carisma Therapeutics Inc., Sysmex Corporation, Takeda Pharmaceutical Company Limited (Japan), and Unitech Medical Inc. He also holds stock ownership in Pear Bio and Phoenix Molecular Designs, and has speaker or preceptorship roles with AstraZeneca Pharmaceuticals LP, Chugai Roche Inc., Daiichi Sankyo Co., Ltd., Kyowa Kirin Co., Ltd., Pfizer Inc., Total Health Conferencing, and Eli Lilly. Additionally, Naoto T. Ueno reports research agreements with AnHeart Therapeutics Inc., Eisai Co., Ltd., Gilead Sciences Inc., Phoenix Molecular Designs, Daiichi Sankyo Inc., Puma Biotechnology Inc., Merck & Co., Oncolys BioPharma Inc., OBI Pharma Inc., ChemDiv Inc., Tolero Pharmaceuticals Inc., and VITRAC Therapeutics LLC. Jangsoon Lee reports scientific advisory role for Astrion Inc. Naoto T. Ueno and Jangsoon Lee have received research grants through their institution from Daiichi Sankyo, Eisai, Duality Biologics, and OBI Pharma. All other authors declare that they have no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"Animal studies were approved by the Institutional Animal Care and Use Committee of MD Anderson Cancer Center (protocol 00001754-RN01). Animal care and experiments were conducted per Institutional and National Institutes of Health guidelines.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}