Abstract
Cell-cell fusion has been implicated in various physiological and pathological processes, including cancer progression. This study investigated the role of cell-cell fusion in non-small cell lung cancer (NSCLC), focusing on its contribution to chemoresistance and tumor evolution. By co-culturing drug-sensitive and drug-resistant NSCLC cell lines, we observed spontaneous cell-cell fusion events, particularly under gefitinib selection. These fused cells exhibited enhanced fitness and a higher degree of chemoresistance compared to parental lines across a panel of 12 chemotherapeutic agents. Further analysis, including fluorescence imaging and cell cycle analysis, confirmed nuclear fusion and increased DNA content in the fused cells. Bulk RNA sequencing revealed genomic heterogeneity in fused cells, including enrichment of gene sets associated with cell cycle progression and epithelial-mesenchymal transition, hallmarks of cancer malignancy. These findings demonstrate that cell-cell fusion contributes significantly to therapeutic resistance and the promotion of aggressive phenotypes in NSCLC, highlighting its potential as a therapeutic target.