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This study aimed to investigate the dynamic changes in HER2 expression during the development and reversal of trastuzumab resistance, and to evaluate the utility of a novel HER2\u2010targeting molecular probe,\n                    <jats:sup>99m<\/jats:sup>\n                    Tc\u2010HP\u2010Ark2, for non\u2010invasive, real\u2010time monitoring of HER2 status and treatment response. Trastuzumab\u2010resistant SK\u2010BR\u20103R cells, established through chronic exposure of parental SK\u2010BR\u20103 cells to increasing concentrations of trastuzumab, exhibited stable resistance (resistance index\u2009=\u200913.79), accompanied by significant upregulation of HER2 and phosphorylated PI3K (p\u2010PI3K) expression. Treatment with the PI3K inhibitor LY294002 effectively inhibited p\u2010PI3K activation and substantially reduced HER2 expression. Notably, the combination of LY294002 with trastuzumab led to a more pronounced downregulation of HER2 and restored trastuzumab sensitivity in SK\u2010BR\u20103R cells. In vivo SPECT\/CT imaging consistently showed significantly higher\n                    <jats:sup>99m<\/jats:sup>\n                    Tc\u2010HP\u2010Ark2 uptake in SK\u2010BR\u20103R tumors compared to SK\u2010BR\u20103 tumors, which markedly decreased upon treatment with LY294002 alone or in combination with trastuzumab. Immunohistochemistry (IHC) analysis confirmed a strong positive correlation between changes in HER2 expression and tumor radioactive uptake trends. This study highlights the pivotal role of HER2 as a dynamic biomarker in trastuzumab resistance and supports the integration of molecular imaging into clinical decision\u2010making for personalized therapeutic adjustments in HER2\u2010positive breast cancer.\n                  <\/jats:p>","DOI":"10.1002\/ijc.70235","type":"journal-article","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T12:49:38Z","timestamp":1764420578000},"page":"1726-1739","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>\n                      <sup>99m<\/sup>\n                      Tc\n                    <\/scp>\n                    \u2010\n                    <scp>HP<\/scp>\n                    \u2010Ark2\n                    <scp>SPECT<\/scp>\n                    \/\n                    <scp>CT<\/scp>\n                    imaging reveals dynamic\n                    <scp>HER2<\/scp>\n                    regulation in trastuzumab resistance and its reversal by\n                    <scp>PI3K<\/scp>\n                    inhibition"],"prefix":"10.1002","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6738-4761","authenticated-orcid":false,"given":"Xiuting","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine, The First Affiliated Hospital Fujian Medical University  Fuzhou Fujian China"},{"name":"Department of Nuclear Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, The First Affiliated Hospital Fujian Medical University  Fuzhou Fujian China"},{"name":"Department of Nuclear Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Thyroid and Breast Surgery, The First Affiliated Hospital Fujian Medical University  Fuzhou Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, The First Affiliated Hospital Fujian Medical University  Fuzhou Fujian China"},{"name":"Department of Nuclear Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital Fujian Medical University  Fuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiyun","family":"Shi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules Institute of Biophysics, Chinese Academy of Sciences  Beijing 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