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Here, we show that high expression of p21-activated kinase 5 (PAK5) is associated with HER2-targeted therapy resistance and poor outcomes of breast cancer patients. Excitingly, we find an increase in N-HER2 protein expression in patients with high PAK5 expression, who demonstrate resistance to trastuzumab treatment. PAK5 phosphorylates methyltransferase METTL14 on serine 399 to enhance m\n                    <jats:sup>6<\/jats:sup>\n                    A modification of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), leading to increased MALAT1 stability. The stabilized MALAT1 inhibits ubiquitin-proteasomal degradation of the N-HER2 by affecting the interaction of deubiquitinase USP8 and N-HER2, thereby promoting N-HER2 accumulation. Moreover, HER2 upregulates the expression of PAK5 and MALAT1, activating the HER2-MALAT1 positive feedback loop. Importantly, PAK5 promotes the therapeutic resistance of HER2-positive breast cancer cells by increasing N-HER2 protein both in vitro and vivo. These findings highlight PAK5 as a therapeutic target for combating trastuzumab resistance in HER2-positive breast cancer.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-07657-2","type":"journal-article","created":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T12:39:41Z","timestamp":1745239181000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["PAK5 promotes the trastuzumab resistance by increasing HER2 nuclear accumulation in HER2-positive breast cancer"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1540-2149","authenticated-orcid":false,"given":"Xin","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5265-2375","authenticated-orcid":false,"given":"Yang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihang","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yidu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chendong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9198-9795","authenticated-orcid":false,"given":"Yuee","family":"Teng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7647-864X","authenticated-orcid":false,"given":"Danni","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5868-7456","authenticated-orcid":false,"given":"Feng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,21]]},"reference":[{"key":"7657_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2022.102436","volume":"109","author":"JZ Drago","year":"2022","unstructured":"Drago JZ, Ferraro E, Abuhadra N, Modi S. 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