Cisplatin-mediated activation of NF-κB promotes lung cancer stem cell formation via DNA repair pathways

Background Cisplatin (DDP) an effective DNA-damaging agent, is fundamental in treating non-small cell lung cancer (NSCLC). Resistance to DDP remains a significant challenge in the treatment of NSCLC. This study aimed to elucidate the mechanisms underlying DDP resistance, with a focus on the role of DNA repair pathways and cancer stem cells (CSCs) in NSCLC. Method We analyzed p-DNA-PKcs expression in 60 lung cancer tissues (30 DDP-resistant and 30 DDP-sensitive tissues). Using in vitro and in vivo models, such as patient-derived organoids (PDOs) and cell line-derived xenografts, we explored the interplay between DNA repair mechanisms, CSC formation, and NF-κB activation in DDP-resistant NSCLC. The therapeutic potential of targeting DNA-PKcs was also explored using the DNA-PKcs inhibitor NU7441. Result Our findings revealed that p-DNA-PKcs is frequently upregulated in DDP-resistant tissues and cell lines and predicts poor prognosis. Activation of the non-homologous end joining (NHEJ) DNA repair pathway by DDP facilitated the stemness of NSCLC. Mechanistically, NF-κB activation was sustained through p300-mediated acetylation of p65 in response to DNA damage, contributing to resistance against DDP. Furthermore, the combination of NU7441 with DDP significantly enhanced the anti-tumor effects in NSCLC models. Conclusion This study revealed that NSCLC cells acquire stemness traits through NF-κB activation, with p-DNA-PKcs-induced phosphorylation of p65 being a prerequisite for p65 acetylation and sustained NF-κB activation in drug-resistant cells. Targeting DNA-PKcs represents a novel and effective treatment strategy to overcome DDP resistance in NSCLC.