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For patients exhibiting non-small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are a first-line treatment. However, most patients who initially responded to EGFR-TKIs eventually developed acquired resistance, limiting the effectiveness of therapy. It has long been known that epithelial–mesenchymal transition (EMT) leads to acquired resistance to EGFR-TKIs in NSCLC. However, the mechanisms underlying the resistance dependent on EMT are unknown. This research aimed to reveal the effects of <i>LMNA</i> in the regulation of acquired resistance to erlotinib by EMT in NSCLC. The acquired erlotinib-resistant cells (HCC827/ER) were induced by gradual increase of concentrations of erlotinib in erlotinib-sensitive HCC827 cells. RNA sequencing and bioinformatics analysis were performed to uncover the involvement of <i>LMNA</i> in the EMT process that induced acquired resistance to erlotinib. The effect of <i>LMNA</i> on cell proliferation and migration was measured by clone-formation, wound-healing, and transwell assays, respectively. The EMT-related protein, nuclear shape and volume, and cytoskeleton changes were examined by immunofluorescence. Western blot was used to identify the underlying molecular mechanism of <i>LMNA</i> regulation of EMT. HCC827/ER cells with acquired resistance to erlotinib underwent EMT and exhibited lower <i>LMNA</i> expression compared to parental sensitive cells. <i>LMNA</i> negatively regulated the expression of EMT markers; HCC827/ER cells showed a significant up-regulation of mesenchymal markers, such as <i>CDH2</i>, <i>SNAI2</i>, <i>VIM</i>, <i>ZEB1</i>, and <i>TWIST1</i>. The overexpression of <i>LMNA</i> in HCC827/ER cells significantly inhibited EMT and cell proliferation, and this inhibitory effect of <i>LMNA</i> was enhanced in the presence of 2.5 μM erlotinib. Furthermore, a decrease in <i>LMNA</i> expression resulted in a higher nuclear deformability and cytoskeletal changes. In HCC827/ER cells, AKT, FGFR, ERK1/2, and c-fos phosphorylation levels were higher than those in HCC827 cells; Furthermore, overexpression of <i>LMNA</i> in HCC827/ER cells reduced the phosphorylation of AKT, ERK1/2, c-fos, and FGFR. In conclusion, our findings first demonstrated that downregulation of <i>LMNA</i> promotes acquired EGFR-TKI resistance in NSCLC with EGFR mutations by EMT. <i>LMNA</i> inhibits cell proliferation and migration of erlotinib-resistant cells via inhibition of the FGFR/MAPK/c-fos signaling pathway. These findings indicated <i>LMNA</i> as a driver of acquired resistance to erlotinib and provided important information about the development of resistance to erlotinib treatment in NSCLC patients with EGFR mutations.