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The tumor suppressor gene <jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7 modulates chemosensitivity in various human cancers. However, its role in <jats:styled-content style=\"fixed-case\">EGFR<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content> therapy in <jats:styled-content style=\"fixed-case\">NSCLC<\/jats:styled-content> has not been well studied. Here, we demonstrate that the mice with deficient <jats:italic>Fbxw7<\/jats:italic> have greater susceptibility to urethane\u2010induced lung tumor development. Through analysis of The Cancer Genome Atlas data, we show that deletion of <jats:italic><jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7<\/jats:italic> occurs in 30.9% of lung adenocarcinomas and 63.5% of lung squamous cell carcinomas, which significantly leads to decrease in <jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7 <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> expression. The reduction in <jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7 <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> level is associated with poor overall survival in lung cancer patients. <jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7 knockdown dramatically promotes epithelial\u2013mesenchymal transition, migration, and invasion in <jats:styled-content style=\"fixed-case\">NSCLC<\/jats:styled-content> cells. Moreover, with silenced <jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7, <jats:styled-content style=\"fixed-case\">EGFR<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>\u2010sensitive cells become resistant to gefitinib, which is reversed by the mammalian target of rapamycin inhibitor, rapamycin. Furthermore, xenograft mouse model studies show that <jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7 knockdown enhances tumorigenesis and resistance to\u00a0gefitinib. Combination of gefitinib with rapamycin treatment suppresses tumor formation of gefitinib\u2010resistant (GR) <jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7\u2010knockdown cells. In conclusion, our findings suggest that loss of <jats:styled-content style=\"fixed-case\">FBXW<\/jats:styled-content>7 promotes <jats:styled-content style=\"fixed-case\">NSCLC<\/jats:styled-content> progression as well as gefitinib resistance and combination of gefitinib and rapamycin may provide an effective therapy for GR NSCLC.<\/jats:p>","DOI":"10.1002\/1878-0261.12200","type":"journal-article","created":{"date-parts":[[2018,4,10]],"date-time":"2018-04-10T04:36:35Z","timestamp":1523334995000},"page":"883-895","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["<scp>FBXW<\/scp>7 deletion contributes to lung tumor development and confers resistance to gefitinib therapy"],"prefix":"10.1002","volume":"12","author":[{"given":"Yi","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Shandong University School of Basic Medical Sciences Jinan 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