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Our team developed limertinib (ASK120067), a novel third\u2010generation EGFR inhibitor with remarkable antitumor effects, which has been launched in China. Despite initial therapeutic responses, EGFR TKIs\u2010treated patients ultimately experience fatal metastatic recurrence and disease progression. However, the underlying mechanism of driving metastasis remains poorly understood. Here, we aim to investigate the pro\u2010metastatic mechanism following treatment with third\u2010generation EGFR TKIs. Transcriptomics analyses of EGFR TKI\u2010resistant tumor models revealed an aberrant upregulation of S1PR3, which conferred enhanced metastatic potential to lung cancer. S1PR3 inhibition dramatically reduced metastasis in resistant cells, while its overexpression potentiated metastatic abilities in parental cells. Notably, S1PR3 was highly enriched in clinical samples with AZD9291 resistance and correlates with poor prognosis. Mechanistically, we found that S1PR3 upregulated RAC1\u2010GTP expression to activate PAK1, thereby promoting epithelial\u2010mesenchymal transition (EMT) and enhancing metastatic capacity of resistant cells. Further studies identified that the overexpression of fibroblast growth factor receptor 1 (FGFR1) increased S1PR3 expression through signal transducer and activator of transcription 4 (STAT4) to promote the emergence of metastatic\u2010resistant cells. Importantly, targeting S1PR3 or FGFR1 blocks metastasis in EGFR TKI\u2010resistant models.<\/jats:p>","DOI":"10.1002\/mco2.70744","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T04:46:08Z","timestamp":1777005968000},"source":"Crossref","is-referenced-by-count":1,"title":["Sphingosine\u20101\u2010Phosphate Receptor 3 Confers Tumor Metastasis in Lung Cancer Resistant to Third\u2010Generation EGFR Inhibitor"],"prefix":"10.1002","volume":"7","author":[{"given":"Mengzhen","family":"Lai","sequence":"first","affiliation":[{"name":"Division of Antitumor Pharmacology &amp; State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"},{"name":"Department of Pharmacology School of Pharmacy Fudan University  Shanghai China"},{"name":"University of Chinese Academy of Sciences  Beijing 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