{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T13:18:57Z","timestamp":1787750337432,"version":"build-2784847793"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>This study addresses the safety profiles and molecular mechanisms of trastuzumab monotherapy and its combination with lapatinib, neratinib, and tucatinib for treating HER2-positive tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The research integrates a multi-platform approach, including data from the US Food and Drug Administration Adverse Event Reporting System (FAERS), network pharmacology, molecular docking, molecular dynamics simulations, and\n                      <jats:italic>in vitro<\/jats:italic>\n                      experiments. Specifically, 38,300 FAERS reports were screened, alongside a series of\n                      <jats:italic>in silico<\/jats:italic>\n                      modeling and laboratory assays to systematically evaluate drug safety and therapeutic mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Pharmacovigilance analysis revealed that trastuzumab monotherapy was associated with an elevated incidence of cardiac and tumor progression-related adverse events (AEs). Combination therapies showed longer adverse event latency periods. Network pharmacology identified HSP90AA1 as a pivotal therapeutic target, while molecular docking and 100-ns molecular dynamics simulations confirmed the stable binding of each drug to HSP90AA1.\n                      <jats:italic>In vitro<\/jats:italic>\n                      assays demonstrated that HSP90AA1 is significantly overexpressed in breast cancer, driving cell proliferation and invasion, and correlates with a poor prognosis. Furthermore, the triple regimen of trastuzumab, lapatinib, and tanespimycin significantly inhibited the PI3K\/Akt\/mTOR signaling pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study establishes a novel framework for drug safety evaluation and provides a theoretical rationale for optimizing therapeutic strategies in HER2-positive tumors. These findings highlight the potential advantages of combination therapies regarding AE latency and elucidate the critical role of HSP90AA1.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1844013","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T12:25:32Z","timestamp":1787747132000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Trastuzumab-TKI combination in HER2-Positive tumors: a FAERS-Based safety profile and multimodal analysis of Tanespimycin\u2019s role in enhancing targeting of the HSP90AA1-PI3K-Akt-mTOR axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiao","family":"Chen","sequence":"first","affiliation":[{"name":"The First Department of Breast Cancer, Tianjin\u2019s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Han","sequence":"additional","affiliation":[{"name":"The First Department of Breast Cancer, Tianjin\u2019s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Department of Breast Cancer, Tianjin\u2019s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junming","family":"Cao","sequence":"additional","affiliation":[{"name":"The First Department of Breast Cancer, Tianjin\u2019s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"The First Department of Breast Cancer, Tianjin\u2019s Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"918993","DOI":"10.3389\/fonc.2022.918993","article-title":"C-reactive protein provides superior prognostic accuracy than the IMDC risk model in renal cell carcinoma treated with atezolizumab\/Bevacizumab","volume":"12","author":"Abuhelwa","year":"2022","journal-title":"Front. 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