{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:27:34Z","timestamp":1790645254716,"version":"4.1.0"},"reference-count":65,"publisher":"American Association for Cancer Research (AACR)","issue":"8","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":123,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["202110MFE-472650-242151"],"award-info":[{"award-number":["202110MFE-472650-242151"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009326","name":"Cancer Research Society","doi-asserted-by":"publisher","award":["1505135"],"award-info":[{"award-number":["1505135"]}],"id":[{"id":"10.13039\/100009326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P50CA168504"],"award-info":[{"award-number":["P50CA168504"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R35 CA197623"],"award-info":[{"award-number":["R35 CA197623"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P01 CA250959"],"award-info":[{"award-number":["P01 CA250959"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R35 CA305086"],"award-info":[{"award-number":["R35 CA305086"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1S10OD036228-01"],"award-info":[{"award-number":["1S10OD036228-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,8,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Intratumor heterogeneity for human epidermal growth factor receptor 2 (HER2) in HER2-positive breast cancer is a driver of resistance to HER2-targeted therapies. The advancement of treatments for HER2 heterogeneous (HET) tumors has been hindered by the lack of preclinical models that accurately mimic the human disease. In this study, we describe human HER2 HET breast cancer models composed of ERBB2-amplified (HER2hi) and nonamplified (HER2lo) cell populations derived from the same tumor. Utilizing these models, together with cellular barcoding, we demonstrate subclonal cooperation between HER2hi and HER2lo subpopulations. Furthermore, HER2lo cells drive resistance to HER2-targeting antibody\u2013drug conjugates (ADC) like trastuzumab deruxtecan (T-DXd) but are sensitive to HER2 kinase inhibitors. CRISPR screens in HET cocultures identified sensitizers of HER2lo cells to T-DXd, including ATP-binding cassette subfamily C member 1 and ubiquitin-specific peptidase 9 X (USP9X). USP9X inhibition enhances the lysosomal targeting of HER2, thereby potentiating ADC payload release and reducing tumor recurrence after T-DXd treatment. Our results elucidate the functional relevance of HER2 heterogeneity and propose improved therapies for these tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Studies of HER2 HET breast cancer models demonstrated that HER2lo cells drive HER2-targeting ADC resistance and accelerate recurrence by cooperating with HER2hi cells. We identified novel therapeutic strategies to sensitize HER2lo cells to T-DXd, providing mechanistic insight and offering promising avenues to overcome resistance and improve patient outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-1459","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T14:01:57Z","timestamp":1775138517000},"page":"1691-1710","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["HER2 Heterogeneous Breast Cancer Models Reveal Novel Therapeutic Targets and Subclonal Dynamics during Evolution to Resistance to HER2-Targeted Therapies"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3199-2252","authenticated-orcid":false,"given":"Marie-Anne","family":"Goyette","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 1 Department of Medical Oncology, , Boston, Massachusetts."},{"name":"2Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"3Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8552-7767","authenticated-orcid":false,"given":"Christopher","family":"Graser","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 4 Department of Data Science, , Boston, Massachusetts."},{"name":"5Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts."},{"name":"6Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0440-6967","authenticated-orcid":false,"given":"Marco","family":"Seehawer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 1 Department of Medical Oncology, , Boston, Massachusetts."},{"name":"2Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"3Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7813-0592","authenticated-orcid":false,"given":"Andriana","family":"Patmanidis","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 4 Department of Data Science, , Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2311-0205","authenticated-orcid":false,"given":"Ernesto","family":"Rojas Jimenez","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 1 Department of Medical Oncology, , Boston, Massachusetts."},{"name":"2Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"3Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3673-553X","authenticated-orcid":false,"given":"Avni","family":"Kamat","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 1 Department of Medical Oncology, , Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8142-0944","authenticated-orcid":false,"given":"Pengze","family":"Yan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 1 Department of Medical Oncology, , Boston, Massachusetts."},{"name":"2Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"3Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2777-0585","authenticated-orcid":false,"given":"Anne","family":"Fassl","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 7 Department of Cancer Biology, , Boston, Massachusetts."},{"name":"8Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4198-271X","authenticated-orcid":false,"given":"Pierre","family":"Foidart","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 1 Department of Medical Oncology, , Boston, Massachusetts."},{"name":"2Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"3Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1213-640X","authenticated-orcid":false,"given":"Zheqi","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 1 Department of Medical Oncology, , Boston, Massachusetts."},{"name":"2Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"3Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0097-9311","authenticated-orcid":false,"given":"Ameera","family":"James","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 1 Department of Medical Oncology, , Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2972-0549","authenticated-orcid":false,"given":"George","family":"Sflomos","sequence":"additional","affiliation":[{"name":"9Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL), Lausanne, Switzerland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6857-3230","authenticated-orcid":false,"given":"Cathrin","family":"Brisken","sequence":"additional","affiliation":[{"name":"9Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne (EPFL), Lausanne, Switzerland."},{"name":"10Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8859-5234","authenticated-orcid":false,"given":"Piotr","family":"Sicinski","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 7 Department of Cancer Biology, , Boston, Massachusetts."},{"name":"8Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4869-8842","authenticated-orcid":false,"given":"Franziska","family":"Michor","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 4 Department of Data Science, , Boston, Massachusetts."},{"name":"5Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts."},{"name":"6Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts."},{"name":"11The Broad Institute of MIT and Harvard, Cambridge, Massachusetts."},{"name":"12The Ludwig Center at Harvard, Boston, Massachusetts."},{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 13 The Center for Cancer Evolution, , Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5964-0382","authenticated-orcid":false,"given":"Kornelia","family":"Polyak","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 1 Department of Medical Oncology, , Boston, Massachusetts."},{"name":"2Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"3Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts."},{"name":"11The Broad Institute of MIT and Harvard, Cambridge, Massachusetts."},{"name":"12The Ludwig Center at Harvard, Boston, Massachusetts."},{"id":[{"id":"https:\/\/ror.org\/02jzgtq86","id-type":"ROR","asserted-by":"publisher"}],"name":"Dana-Farber Cancer Institute 13 The Center for Cancer Evolution, , Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1086","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"2026080303132117000_bib1","doi-asserted-by":"crossref","first-page":"5321","DOI":"10.1073\/pnas.89.12.5321","article-title":"ERBB2 amplification in breast cancer analyzed by fluorescence in situ hybridization","volume":"89","author":"Kallioniemi","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026080303132117000_bib2","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1126\/science.2470152","article-title":"Studies of the HER-2\/neu proto-oncogene in human breast and ovarian cancer","volume":"244","author":"Slamon","year":"1989","journal-title":"Science"},{"key":"2026080303132117000_bib3","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1056\/NEJMcibr1909386","article-title":"HER2 and breast cancer \u2014 a phenomenal success story","volume":"381","author":"Hayes","year":"2019","journal-title":"N Engl J Med"},{"key":"2026080303132117000_bib4","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1056\/NEJMoa1703643","article-title":"Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer","volume":"377","author":"von Minckwitz","year":"2017","journal-title":"N Engl J Med"},{"key":"2026080303132117000_bib5","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s11912-024-01628-0","article-title":"Antibody-drug conjugates in breast cancer: the road towards biologically-informed selection and sequencing","volume":"27","author":"O\u2019Meara","year":"2025","journal-title":"Curr Oncol Rep"},{"key":"2026080303132117000_bib6","doi-asserted-by":"crossref","first-page":"3996","DOI":"10.3390\/cancers14163996","article-title":"Overcoming resistance to HER2-directed therapies in breast cancer","volume":"14","author":"Schlam","year":"2022","journal-title":"Cancers (Basel)"},{"key":"2026080303132117000_bib7","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1158\/1541-7786.MCR-19-0582","article-title":"Antibody\u2013drug conjugates: a comprehensive review","volume":"18","author":"Khongorzul","year":"2020","journal-title":"Mol Cancer Res"},{"key":"2026080303132117000_bib8","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1158\/2159-8290.CD-24-0708","article-title":"The journey of antibody\u2013drug conjugates: lessons learned from 40 years of development","volume":"14","author":"Colombo","year":"2024","journal-title":"Cancer Discov"},{"key":"2026080303132117000_bib9","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1158\/2159-8290.CD-20-1557","article-title":"Impact of HER2 heterogeneity on treatment response of early-stage HER2-positive breast cancer: phase II neoadjuvant clinical trial of T-DM1 combined with pertuzumab","volume":"11","author":"Filho","year":"2021","journal-title":"Cancer Discov"},{"key":"2026080303132117000_bib10","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1309\/AJCPIRL4GUVGK3YX","article-title":"HER2 heterogeneity affects trastuzumab responses and survival in patients with HER2-positive metastatic breast cancer","volume":"142","author":"Lee","year":"2014","journal-title":"Am J Clin Pathol"},{"key":"2026080303132117000_bib11","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.3390\/cancers16051062","article-title":"High HER2 intratumoral heterogeneity is a predictive factor for poor prognosis in early-stage and locally advanced HER2-positive breast cancer","volume":"16","author":"Tanei","year":"2024","journal-title":"Cancers"},{"key":"2026080303132117000_bib12","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1002\/1878-0261.12375","article-title":"Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors","volume":"12","author":"Rye","year":"2018","journal-title":"Mol Oncol"},{"key":"2026080303132117000_bib13","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1200\/JCO.2013.50.9984","article-title":"Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology\/College of American Pathologists clinical practice guideline update","volume":"31","author":"Wolff","year":"2013","journal-title":"J Clin Oncol"},{"key":"2026080303132117000_bib14","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat Genet"},{"key":"2026080303132117000_bib15","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1111\/cas.12966","article-title":"Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity","volume":"107","author":"Ogitani","year":"2016","journal-title":"Cancer Sci"},{"key":"2026080303132117000_bib16","doi-asserted-by":"crossref","first-page":"e176454","DOI":"10.1172\/JCI176454","article-title":"HER2 heterogeneity and treatment response-associated profiles in HER2-positive breast cancer in the NCT02326974 clinical trial","volume":"134","author":"Li","year":"2024","journal-title":"J Clin Invest"},{"key":"2026080303132117000_bib17","first-page":"7351","article-title":"Tumor progression in four mammary epithelial cell lines derived from the same patient","volume":"50","author":"Band","year":"1990","journal-title":"Cancer Res"},{"key":"2026080303132117000_bib18","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1002\/(SICI)1097-0215(19981209)78:6<766::AID-IJC15>3.0.CO;2-L","article-title":"Characterization of paired tumor and non-tumor cell lines established from patients with breast cancer","volume":"78","author":"Gazdar","year":"1998","journal-title":"Int J Cancer"},{"key":"2026080303132117000_bib19","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/35021093","article-title":"Molecular portraits of human breast tumours","volume":"406","author":"Perou","year":"2000","journal-title":"Nature"},{"key":"2026080303132117000_bib20","doi-asserted-by":"crossref","first-page":"e147617","DOI":"10.1172\/jci.insight.147617","article-title":"The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2+ breast cancer","volume":"6","author":"Janiszewska","year":"2021","journal-title":"JCI Insight"},{"key":"2026080303132117000_bib21","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.annonc.2024.07.245","article-title":"Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022","volume":"35","author":"Freedman","year":"2024","journal-title":"Ann Oncol"},{"key":"2026080303132117000_bib22","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1158\/2159-8290.CD-20-0215","article-title":"HER2-mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers","volume":"10","author":"Li","year":"2020","journal-title":"Cancer Discov"},{"key":"2026080303132117000_bib23","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/s43018-021-00222-8","article-title":"Multifunctional barcoding with ClonMapper enables high-resolution study of clonal dynamics during tumor evolution and treatment","volume":"2","author":"Gutierrez","year":"2021","journal-title":"Nat Cancer"},{"key":"2026080303132117000_bib24","doi-asserted-by":"crossref","first-page":"e107333","DOI":"10.15252\/embj.2020107333","article-title":"A single-cell RNA expression atlas of normal, preneoplastic and tumorigenic states in the human breast","volume":"40","author":"Pal","year":"2021","journal-title":"Embo J"},{"key":"2026080303132117000_bib25","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1186\/s13059-014-0554-4","article-title":"MAGeCK enables robust identification of essential genes from genome-scale CRISPR\/Cas9 knockout screens","volume":"15","author":"Li","year":"2014","journal-title":"Genome Biol"},{"key":"2026080303132117000_bib26","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1093\/jnci\/92.16.1295","article-title":"A family of drug transporters: the multidrug resistance-associated proteins","volume":"92","author":"Borst","year":"2000","journal-title":"J Natl Cancer Inst"},{"key":"2026080303132117000_bib27","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1158\/1535-7163.MCT-14-0862","article-title":"Tumor cells chronically treated with a trastuzumab-maytansinoid antibody-drug conjugate develop varied resistance mechanisms but respond to alternate treatments","volume":"14","author":"Loganzo","year":"2015","journal-title":"Mol Cancer Ther"},{"key":"2026080303132117000_bib28","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1038\/ng.3391","article-title":"In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer","volume":"47","author":"Janiszewska","year":"2015","journal-title":"Nat Genet"},{"key":"2026080303132117000_bib29","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/S1470-2045(24)00128-1","article-title":"Trastuzumab deruxtecan versus treatment of physician\u2019s choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial","volume":"25","author":"Fehm","year":"2024","journal-title":"Lancet Oncol"},{"key":"2026080303132117000_bib30","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1056\/NEJMoa2203690","article-title":"Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer","volume":"387","author":"Modi","year":"2022","journal-title":"N Engl J Med"},{"issue":"17_suppl","key":"2026080303132117000_bib31","doi-asserted-by":"crossref","first-page":"LBA1008","DOI":"10.1200\/JCO.2025.43.17_suppl.LBA1008","article-title":"Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2\u2013positive (HER2+) advanced\/metastatic breast cancer (a\/mBC): interim results from DESTINY-Breast09","volume":"43","author":"Tolaney","year":"2025","journal-title":"J Clin Oncol"},{"key":"2026080303132117000_bib32","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1158\/2159-8290.CD-25-0647","article-title":"Trastuzumab deruxtecan resistance via loss of HER2 expression and binding","volume":"16","author":"Chen","year":"2026","journal-title":"Cancer Discov"},{"key":"2026080303132117000_bib33","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.3390\/cancers15041130","article-title":"Resistance to antibody-drug conjugates targeting HER2 in breast cancer: molecular landscape and future challenges","volume":"15","author":"Guidi","year":"2023","journal-title":"Cancers (Basel)"},{"key":"2026080303132117000_bib34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.drup.2016.03.001","article-title":"ABC transporters as mediators of drug resistance and contributors to cancer cell biology","volume":"26","author":"Fletcher","year":"2016","journal-title":"Drug Resist Updat"},{"key":"2026080303132117000_bib35","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s10555-012-9402-8","article-title":"Reversal of ATP-binding cassette drug transporter activity to modulate chemoresistance: why has it failed to provide clinical benefit?","volume":"32","author":"Yu","year":"2013","journal-title":"Cancer Metastasis Rev"},{"key":"2026080303132117000_bib36","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.cell.2008.10.051","article-title":"FAM\/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination","volume":"136","author":"Dupont","year":"2009","journal-title":"Cell"},{"key":"2026080303132117000_bib37","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.cub.2015.11.050","article-title":"USP9X controls EGFR fate by deubiquitinating the endocytic adaptor Eps15","volume":"26","author":"Savio","year":"2016","journal-title":"Curr Biol"},{"key":"2026080303132117000_bib38","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1038\/s41388-018-0134-2","article-title":"The deubiquitinase USP9X promotes tumor cell survival and confers chemoresistance through YAP1 stabilization","volume":"37","author":"Li","year":"2018","journal-title":"Oncogene"},{"key":"2026080303132117000_bib39","doi-asserted-by":"crossref","first-page":"e2101592118","DOI":"10.1073\/pnas.2101592118","article-title":"Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer","volume":"118","author":"Jaiswal","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026080303132117000_bib40","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nature08646","article-title":"Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival","volume":"463","author":"Schwickart","year":"2010","journal-title":"Nature"},{"key":"2026080303132117000_bib41","doi-asserted-by":"crossref","first-page":"e2039","DOI":"10.1038\/cddis.2015.405","article-title":"Deubiquitylating enzyme USP9x regulates radiosensitivity in glioblastoma cells by Mcl-1-dependent and -independent mechanisms","volume":"7","author":"Wolfsperger","year":"2016","journal-title":"Cell Death Dis"},{"key":"2026080303132117000_bib42","doi-asserted-by":"crossref","first-page":"851","DOI":"10.15252\/emmm.201506047","article-title":"USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma","volume":"8","author":"Engel","year":"2016","journal-title":"EMBO Mol Med"},{"key":"2026080303132117000_bib43","doi-asserted-by":"crossref","first-page":"3709","DOI":"10.1158\/0008-5472.CAN-09-3768","article-title":"ErbB2 trafficking and degradation associated with K48 and K63 polyubiquitination","volume":"70","author":"Marx","year":"2010","journal-title":"Cancer Res"},{"key":"2026080303132117000_bib44","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1158\/0008-5472.CAN-24-2021","article-title":"Perivascular niche-resident alveolar macrophages promote interstitial pneumonitis related to trastuzumab deruxtecan treatment","volume":"85","author":"Wei","year":"2025","journal-title":"Cancer Res"},{"key":"2026080303132117000_bib45","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1038\/s41591-023-02478-2","article-title":"Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial","volume":"29","author":"Mosele","year":"2023","journal-title":"Nat Med"},{"key":"2026080303132117000_bib46","doi-asserted-by":"crossref","first-page":"103699","DOI":"10.1016\/j.esmoop.2024.103699","article-title":"Trastuzumab deruxtecan in patients with previously treated HER2-low advanced breast cancer and active brain metastases: the DEBBRAH trial","volume":"9","author":"Vaz Batista","year":"2024","journal-title":"ESMO Open"},{"key":"2026080303132117000_bib47","doi-asserted-by":"crossref","first-page":"100299","DOI":"10.1016\/j.modpat.2023.100299","article-title":"HER2 genetic intratumor heterogeneity is associated with resistance to trastuzumab and trastuzumab emtansine therapy in recurrent high-grade endometrial cancer","volume":"36","author":"Shen","year":"2023","journal-title":"Mod Pathol"},{"key":"2026080303132117000_bib48","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1007\/s10120-023-01417-x","article-title":"Down-regulation of stimulator of interferon genes (STING) expression and CD8+ T-cell infiltration depending on HER2 heterogeneity in HER2-positive gastric cancer","volume":"26","author":"Fukai","year":"2023","journal-title":"Gastric Cancer"},{"key":"2026080303132117000_bib49","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The ensembl variant effect predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol"},{"key":"2026080303132117000_bib50","doi-asserted-by":"crossref","first-page":"e1004873","DOI":"10.1371\/journal.pcbi.1004873","article-title":"CNVkit: genome-wide copy number detection and visualization from targeted DNA sequencing","volume":"12","author":"Talevich","year":"2016","journal-title":"PLoS Comput Biol"},{"key":"2026080303132117000_bib51","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s12859-018-2139-9","article-title":"VIPER: visualization Pipeline for RNA-seq, a Snakemake workflow for efficient and complete RNA-seq analysis","volume":"19","author":"Cornwell","year":"2018","journal-title":"BMC Bioinformatics"},{"key":"2026080303132117000_bib52","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"2026080303132117000_bib53","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1093\/bioinformatics\/bts356","article-title":"RSeQC: quality control of RNA-seq experiments","volume":"28","author":"Wang","year":"2012","journal-title":"Bioinformatics"},{"key":"2026080303132117000_bib54","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"2026080303132117000_bib55","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026080303132117000_bib56","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst"},{"key":"2026080303132117000_bib57","doi-asserted-by":"crossref","first-page":"4975","DOI":"10.1038\/s41467-022-32523-6","article-title":"Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence","volume":"13","author":"Aouad","year":"2022","journal-title":"Nat Commun"},{"key":"2026080303132117000_bib58","doi-asserted-by":"crossref","first-page":"108566","DOI":"10.1016\/j.celrep.2020.108566","article-title":"Aging-associated alterations in mammary epithelia and stroma revealed by single-cell RNA sequencing","volume":"33","author":"Li","year":"2020","journal-title":"Cell Rep"},{"key":"2026080303132117000_bib59","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nbt.3192","article-title":"Spatial reconstruction of single-cell gene expression data","volume":"33","author":"Satija","year":"2015","journal-title":"Nat Biotechnol"},{"key":"2026080303132117000_bib60","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat Commun"},{"key":"2026080303132117000_bib61","doi-asserted-by":"crossref","first-page":"3","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","author":"Martin","year":"2011","journal-title":"EMBnet J"},{"key":"2026080303132117000_bib62","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1186\/s12864-016-3195-z","article-title":"Visualizing tumor evolution with the fishplot package for R","volume":"17","author":"Miller","year":"2016","journal-title":"BMC Genomics"},{"key":"2026080303132117000_bib63","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/978-981-32-9755-5_7","article-title":"Analytical platforms 3: processing samples via the RPPA pipeline to generate large-scale data for clinical studies","volume":"1188","author":"Siwak","year":"2019","journal-title":"Adv Exp Med Biol"},{"key":"2026080303132117000_bib64","doi-asserted-by":"crossref","first-page":"5131","DOI":"10.1093\/bioinformatics\/btac665","article-title":"Rppa space: an R package for normalization and quantitation of Reverse-Phase Protein Array data","volume":"38","author":"Shehwana","year":"2022","journal-title":"Bioinformatics"},{"key":"2026080303132117000_bib65","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nmeth.3047","article-title":"Improved vectors and genome-wide libraries for CRISPR screening","volume":"11","author":"Sanjana","year":"2014","journal-title":"Nat Methods"}],"container-title":["Cancer Discovery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/aacrjournals.org\/cancerdiscovery\/article-pdf\/doi\/10.1158\/2159-8290.CD-25-1459\/3761999\/cd-25-1459.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/aacrjournals.org\/cancerdiscovery\/article-pdf\/doi\/10.1158\/2159-8290.CD-25-1459\/3804293\/cd-25-1459.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/aacrjournals.org\/cancerdiscovery\/article-pdf\/16\/8\/1691\/3818204\/cd-25-1459.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/aacrjournals.org\/cancerdiscovery\/article-pdf\/16\/8\/1691\/3818204\/cd-25-1459.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T07:13:43Z","timestamp":1785741223000},"score":1,"resource":{"primary":{"URL":"https:\/\/aacrjournals.org\/cancerdiscovery\/article\/16\/8\/1691\/787128\/HER2-Heterogeneous-Breast-Cancer-Models-Reveal"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,2]]},"references-count":65,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,4,2]]},"published-print":{"date-parts":[[2026,8,3]]}},"URL":"https:\/\/doi.org\/10.1158\/2159-8290.cd-25-1459","relation":{"is-supplemented-by":[{"id-type":"doi","id":"10.1158\/2159-8290.33143021","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.33142991","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.33142994","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.33143018","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.33143006","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.33143015","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.33143003","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.33143024","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.33143000","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.33143012","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.33142997","asserted-by":"object"},{"id-type":"doi","id":"10.1158\/2159-8290.33142988","asserted-by":"object"}],"has-preprint":[{"id-type":"doi","id":"10.1158\/2159-8290.c.8630720","asserted-by":"object"}]},"ISSN":["2159-8274","2159-8290"],"issn-type":[{"value":"2159-8274","type":"print"},{"value":"2159-8290","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,2]]}}}