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However, there are problems with both primary and secondary resistance to trastuzumab. In this study, we employed the human gastric carcinoma cell line NCI-N87 with high Her-2 expression to create trastuzumab-resistant NCI-N87\/TR cells by stepwise exposure to increasing doses of trastuzumab. Western blotting and Real-time PCR were conducted to detect protein and gene levels. Compared with NCI-N87 cells, the expression of P-IGF-1R and P-AKT proteins was significantly increased in NCI-N87\/TR cells (both <jats:italic>P<\/jats:italic>\u2009=\u20090.000), while PTEN gene and protein expression showed a significant decrease (both <jats:italic>P<\/jats:italic>\u2009=\u20090.000). In addition, mutations of the PTEN gene were detected at exons 5, 7 and 8. The sensitivity of NCI-N87\/TR cells to trastuzumab was increased by transfection with the PTEN gene, or by incubation with a PI3K inhibitor (LY294002) or an IGF-IR inhibitor (AG1024), as well as siRNA targeting PI3K p110 or IGF-1R. Taken together, our findings showed that activation of the PI3K-AKT signaling pathway was one of the major mechanisms leading to resistance of NCI-N87\/TR gastric cancer cells to trastuzumab, which was probably associated with PTEN gene down-regulation and mutation, as well as with over-activity of the IGF-1R signaling pathway.<\/jats:p>","DOI":"10.1038\/srep11634","type":"journal-article","created":{"date-parts":[[2015,6,25]],"date-time":"2015-06-25T11:00:25Z","timestamp":1435230025000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Development of trastuzumab-resistant human gastric carcinoma cell lines and mechanisms of drug resistance"],"prefix":"10.1038","volume":"5","author":[{"given":"Qiang","family":"Zuo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengwan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangjun","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,6,25]]},"reference":[{"key":"BFsrep11634_CR1","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.jconrel.2010.04.009","volume":"146","author":"W Tai","year":"2010","unstructured":"Tai, W., Mahato, R. & Cheng, K. 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