Targeting Dual-specificity Phosphatase 23 to Overcome Chemoresistance and Stem Cell-like Behavior in Non-small Cell Lung Cancer Cells

Chemoresistance poses a significant challenge in treating non-small cell lung cancer (NSCLC), often leading to poor outcomes. This resistance is closely linked to cancer stem cell (CSC)-like characteristics, including the ability to evade anoikis. In this study, we identified dual-specificity phosphatase 23 (DUSP23) as a key molecule involved in regulating CSC traits and chemoresistance. DUSP23 expression was significantly elevated in cell clusters grown under ultra-low adhesion (ULA) conditions that mimic CSC-promoting environments. Silencing DUSP23 reduced the formation of these clusters, suppressed the expression of the stemness markers SOX2, and enhanced anoikis sensitivity. Additionally, in cisplatin-resistant NSCLC cells, knockdown of DUSP23 decreased invasive behavior and induced apoptosis. These findings suggest that DUSP23 plays a pivotal role in maintaining CSC-like properties and chemoresistance by regulating SOX2. Targeting DUSP23 could offer a novel approach to overcome treatment resistance and improve outcomes for patients with NSCLC. Overall design: We performed RNA sequencing analysis on A549 cell clusters with the knockdown of DUSP23, compared to control cell clusters.