2. Academic Validation
  3. Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis

Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis

  • Cell Death Dis. 2025 Jun 17;16(1):452. doi: 10.1038/s41419-025-07770-2.
Gaoyan Tang # 1,  Xuelei Cao # 2 3,  Jiaqi Chen # 4,  Fu Hui 1,  Na Xu 1,  Yiqing Jiang 1,  Hongmin Lu 5,  Haifeng Xiao 1,  Xiuming Liang 6 7 8,  Mingzhe Ma 9,  Yu Qian 10,  Dongli Liu 11,  Zhenlu Wang 1,  Shuzhen Liu 12,  Guohua Yu 13,  Lei Sun 14
Affiliations

Affiliations

  • 1 Department of Oncology, Weifang People's Hospital, the First Affiliated Hospital of Shandong Second Medical University, Weifang, China.
  • 2 Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China.
  • 3 Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, Shandong, China.
  • 4 Cancer Prevention and Treatment Center, The Second Hospital of Shandong University, Jinan, China.
  • 5 Department of Oncology, Shanghai Renji Hospital, Shanghai Jiaotong University medical school, Shanghai, China.
  • 6 Division for Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 7 Karolinska ATMP Center, ANA Futura, Karolinska Institutet, Stockholm, Sweden.
  • 8 Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, Stockholm, Sweden.
  • 9 Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 10 Department of thoracic head and neck medical oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 11 Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiaotong University medical school, Shanghai, China.
  • 12 Department of Oncology, Weifang People's Hospital, the First Affiliated Hospital of Shandong Second Medical University, Weifang, China. liushuzhen_wf@163.com.
  • 13 Department of Oncology, Weifang People's Hospital, the First Affiliated Hospital of Shandong Second Medical University, Weifang, China. ghyry@126.com.
  • 14 Department of Oncology, Weifang People's Hospital, the First Affiliated Hospital of Shandong Second Medical University, Weifang, China. sl786777@126.com.
  • # Contributed equally.
PMID: 40523886 DOI: 10.1038/s41419-025-07770-2
Abstract

Non-small cell lung Cancer (NSCLC) is highly malignant with limited treatment options, largely due to the inherent tumoral heterogeneity and acquired resistance towards chemotherapy and immunotherapy. RG7388, a known MDM2 Inhibitor, exhibited Anticancer activity in TP53-wild-type (TP53WT) NSCLC by triggering the p53/PUMA axis-dependent Apoptosis. However, our study uncovered previously unrecognized p53-independent Anticancer effects of RG7388 in TP53-mutant (TP53mutant) NSCLC, although the underlying mechanisms remained elusive. Here, we demonstrated that RG7388 specifically induced the NOXA/Caspase-3 axis-dependent Apoptosis and gasdermin E (GSDME)-mediated secondary Pyroptosis in TP53mutant NSCLC, as validated through in silico analyses and multiple biological assays. Mechanically, we identified Reactive Oxygen Species (ROS) as the critical mediator in NOXA upregulation and p38 MAPK pathway activation in RG7388 treated TP53mutant NSCLC. This was further supported by the use of ROS scavengers, N-acetylcysteine (NAC), and Ferrostatin-1 (Fer-1), which attenuated these effects. Pharmacologic inhibition of p38 MAPK signaling by SB203580 rescued RG7388-induced ROS-dependent NOXA accumulation and subsequent Apoptosis and Pyroptosis, highlighting the central role of the ROS/phosphorylated p38 MAPK (p-p38)/NOXA/Caspase-3 axis in RG7388-induced TP53mutant NSCLC cell death. Our findings revealed a novel mechanism for selectively targeting mutant p53-derived Cancer through ROS/p-p38-mediated NOXA accumulation, offering potential therapeutic implications given the current lack of direct mutant p53 targeting strategies in Cancer. Furthermore, immunohistochemical (IHC) analysis of an NSCLC tissue microarray confirmed a strong positive correlation between p-p38 and NOXA expression. Clinical data analysis further suggested that the p-p38/NOXA axis might be a potential prognostic biomarker for overall survival (OS) in NSCLC patients.

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