{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T08:35:24Z","timestamp":1771403724724,"version":"3.50.1"},"reference-count":29,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Targeted therapies have revolutionized treatment paradigms for a variety of cancer types; however, challenges including primary and acquired resistance persist, and there remains a high demand for novel treatment options. HER3 (ErbB3), a member of the human epidermal growth factor receptor family of receptor tyrosine kinases, is a target of HER3-DXd, an antibody\u2013drug conjugate currently under clinical investigation. As was previously reported, the cytotoxic activity of HER3-DXd in preclinical models is primarily mediated by the antitumor activity of the released payload. Therefore, we investigated the impact of HER3 expression changes on payload release after HER3-DXd treatment using HER3-positive human cancer cell lines and their xenograft models. In vitro studies showed that the amount of payload released from cells after HER3-DXd treatment was associated with baseline HER3 expression levels, HER3 internalization rate, and turnover rate. In female CAnN.Cg-Foxn1nu\/CrlCrlj mouse models, dose and dosing interval influenced membrane HER3 expression levels and tumor payload concentrations. Furthermore, membrane HER3 was upregulated by tyrosine kinase inhibitor treatment in non-small-cell lung cancer cell lines harboring specific driver mutations, including EGFR-activating mutations, ROS1 fusions, and ALK fusions. The increase in HER3 expression induced by osimertinib treatment was associated with increased payload release in PC-9 cells. Our results indicate that HER3 dynamics, as well as baseline HER3 expression, modulate payload release from HER3-DXd and support combination strategies to potentiate the antitumor activity of HER3-DXd.<\/jats:p>","DOI":"10.3390\/ijms27041930","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T07:50:30Z","timestamp":1771401030000},"page":"1930","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Impact of HER3 Dynamics Altered by HER3-DXd Alone and in Combination with Driver Oncogene Inhibitors on HER3-DXd Efficacy"],"prefix":"10.3390","volume":"27","author":[{"given":"Nagiho","family":"Komatsu","sequence":"first","affiliation":[{"name":"Translational Research Laboratory, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saori","family":"Sato","sequence":"additional","affiliation":[{"name":"Translational Science Department I, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuichi","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Translational Research Laboratory, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sumie","family":"Muramatsu","sequence":"additional","affiliation":[{"name":"Translational Research Laboratory, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pang-Dian","family":"Fan","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Inc., Basking Ridge, 211 Mt. Airy Road, Basking Ridge, NJ 07920, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kumiko","family":"Koyama","sequence":"additional","affiliation":[{"name":"Translational Research Laboratory, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa, Tokyo 140-8710, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1158\/1535-7163.MCT-22-0401","article-title":"SGN-CD228A Is an Investigational CD228-Directed Antibody-Drug Conjugate with Potent Antitumor Activity across a Wide Spectrum of Preclinical Solid Tumor Models","volume":"22","author":"Mazahreh","year":"2023","journal-title":"Mol. Cancer Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13045-025-01704-3","article-title":"Antibody-Drug Conjugates (ADCs): Current and future biopharmaceuticals","volume":"18","author":"Wang","year":"2025","journal-title":"J. Hematol. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/cgt.2008.15","article-title":"The ERBB3 receptor in cancer and cancer gene therapy","volume":"15","author":"Sithanandam","year":"2008","journal-title":"Cancer Gene Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1080\/21645515.2015.1102809","article-title":"Emerging anti-cancer antibodies and combination therapies targeting HER3\/ERBB3","volume":"12","author":"Gaborit","year":"2016","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7692","DOI":"10.1073\/pnas.1002753107","article-title":"ErbB3\/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation","volume":"107","author":"Shi","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1158\/1078-0432.CCR-09-1218","article-title":"HER3 comes of age: New insights into its functions and role in signaling, tumor biology, and cancer therapy","volume":"16","author":"Campbell","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1158\/1078-0432.CCR-13-1549","article-title":"Molecular pathways: HER3 targeted therapy","volume":"20","author":"Gala","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/35052073","article-title":"Untangling the ErbB signalling network","volume":"2","author":"Yarden","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nrc2656","article-title":"Novel anticancer targets: Revisiting ERBB2 and discovering ERBB3","volume":"9","author":"Baselga","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1093\/jnci\/djs501","article-title":"HER3 overexpression and survival in solid tumors: A meta-analysis","volume":"105","author":"Ocana","year":"2013","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/bjc.1996.342","article-title":"C-erbB-3 in human breast carcinoma: Expression and relation to prognosis and established prognostic indicators","volume":"74","author":"Travis","year":"1996","journal-title":"Br. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1038\/sj.bjc.6602865","article-title":"HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients","volume":"93","author":"Cappuzzo","year":"2005","journal-title":"Br. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4103","DOI":"10.1158\/1078-0432.CCR-05-2404","article-title":"Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells","volume":"12","author":"Erjala","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1158\/0008-5472.CAN-08-1056","article-title":"Trastuzumab-induced HER reprogramming in \u201cresistant\u201d breast carcinoma cells","volume":"69","author":"Narayan","year":"2009","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5021","DOI":"10.1073\/pnas.1016140108","article-title":"Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase","volume":"108","author":"Garrett","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1186\/s13046-022-02515-x","article-title":"HER3 in cancer: From the bench to the bedside","volume":"41","author":"Pandiella","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1126\/science.1141478","article-title":"MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling","volume":"316","author":"Engelman","year":"2007","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5069","DOI":"10.1016\/j.bmcl.2016.08.082","article-title":"Wide application of a novel topoisomerase I inhibitor-based drug conjugation technology","volume":"26","author":"Ogitani","year":"2016","journal-title":"Bioorg Med. Chem. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.bmcl.2016.02.020","article-title":"Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads","volume":"26","author":"Nakada","year":"2016","journal-title":"Bioorg Med. Chem. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5550","DOI":"10.1200\/JCO.23.00882","article-title":"Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3-Directed Antibody-Drug Conjugate, in Patients with Previously Treated Human Epidermal Growth Factor Receptor 3-Expressing Metastatic Breast Cancer: A Multicenter, Phase I\/II Trial","volume":"41","author":"Krop","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5363","DOI":"10.1200\/JCO.23.01476","article-title":"HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor-Mutated Non-Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy","volume":"41","author":"Yu","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hafeez, U., Parakh, S., Gan, H.K., and Scott, A.M. (2020). Antibody-Drug Conjugates for Cancer Therapy. Molecules, 25.","DOI":"10.3390\/molecules25204764"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/S0140-6736(19)31774-X","article-title":"Antibody-drug conjugates for cancer","volume":"394","author":"Chau","year":"2019","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7151","DOI":"10.1158\/1078-0432.CCR-19-1745","article-title":"A Novel HER3-Targeting Antibody-Drug Conjugate, U3-1402, Exhibits Potent Therapeutic Efficacy through the Delivery of Cytotoxic Payload by Efficient Internalization","volume":"25","author":"Hashimoto","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1158\/0008-5472.CAN-21-2426","article-title":"EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody-Drug Conjugate HER3-DXd","volume":"82","author":"Haikala","year":"2022","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1158\/1078-0432.CCR-21-3359","article-title":"HER3 Augmentation via Blockade of EGFR\/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non-Small Cell Lung Cancer","volume":"28","author":"Yonesaka","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"(2022). Correction: Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer. Cancer Discov., 12, 1598.","DOI":"10.1158\/2159-8290.CD-22-0365"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1208\/s12248-015-9766-0","article-title":"Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection","volume":"17","author":"Sadekar","year":"2015","journal-title":"AAPS J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1158\/1535-7163.MCT-17-0019","article-title":"Tumor-Associated Macrophages Can Contribute to Antitumor Activity through Fc\u03b3R-Mediated Processing of Antibody-Drug Conjugates","volume":"16","author":"Li","year":"2017","journal-title":"Mol. Cancer Ther."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1930\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T07:51:21Z","timestamp":1771401081000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1930"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,17]]},"references-count":29,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27041930"],"URL":"https:\/\/doi.org\/10.3390\/ijms27041930","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,17]]}}}