2. Academic Validation
  3. Cisplatin-mediated activation of NF-κB promotes lung cancer stem cell formation via DNA repair pathways

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

  • J Transl Med. 2025 Nov 21;23(1):1336. doi: 10.1186/s12967-025-07282-9.
Lingyu Zhang # 1 2 3,  Qiumei Li # 1 2,  Chunjiang Liu # 3,  ShiZhong Wu 4,  Guibin Weng 5,  Ling Wang 1 2,  Mingshui Chen 6 7,  Wansong Lin 8 9 10 11
Affiliations

Affiliations

  • 1 Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
  • 2 Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, China.
  • 3 College of Chemistry, Fuzhou University, Fuzhou, 350108, China.
  • 4 Department of Radiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian Province, 350014, China.
  • 5 Department of Thoracic Oncology Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China.
  • 6 Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China. [email protected].
  • 7 Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, China. [email protected].
  • 8 Laboratory of Immuno-Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, China. [email protected].
  • 9 Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, 350014, China. [email protected].
  • 10 College of Chemistry, Fuzhou University, Fuzhou, 350108, China. [email protected].
  • 11 The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, China. [email protected].
  • # Contributed equally.
PMID: 41272697 DOI: 10.1186/s12967-025-07282-9
Abstract

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.

Keywords

Cisplatin resistance; DNA repair; DNA-PKcs; Lung cancer stem cells; NF-κB.

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