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Background <p>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.</p> Method <p>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.</p> Result <p>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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • Lingyu Zhang,
  • Qiumei Li,
  • Chunjiang Liu,
  • ShiZhong Wu,
  • Guibin Weng,
  • Ling Wang,
  • Mingshui Chen,
  • Wansong Lin

摘要

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.