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

## TL;DR

This study shows how lung cancer cells become resistant to cisplatin by activating DNA repair pathways and cancer stem cell traits, and suggests targeting DNA-PKcs as a new treatment strategy.

## Contribution

The study identifies a novel mechanism of cisplatin resistance in lung cancer involving NF-κB activation and DNA repair pathways, and proposes DNA-PKcs inhibition as a potential therapeutic approach.

## Key findings

- p-DNA-PKcs is upregulated in cisplatin-resistant lung cancer tissues and predicts poor prognosis.
- NF-κB activation via p300-mediated acetylation of p65 contributes to cisplatin resistance and stemness in NSCLC.
- Combining DNA-PKcs inhibitor NU7441 with cisplatin enhances anti-tumor effects in NSCLC models.

## Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1186/s12967-025-07282-9.