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

PMCID: PMC12170848

PMID: 40523886

DOI: 10.1038/s41419-025-07770-2

Journal: Cell death & disease

Publication Date: 2025-6-17

Authors: Tang G, Cao X, Chen J, Hui F, Xu N, et al.

Key Points

• RG7388 exhibits potent anti-tumor effects in TP53-mutant NSCLC through a p53-independent mechanism
• Significant dose-dependent reduction in cell viability across four TP53-mutant cell lines (IC50 values demonstrated in study)
• Potential therapeutic strategy for NSCLC patients with mutant p53 and limited treatment options

Summary

This preclinical study investigated RG7388, an MDM2 inhibitor, as a novel therapeutic approach for non-small cell lung cancer (NSCLC) with TP53 mutations. Unlike previous research focusing on wild-type p53 contexts, the study revealed a unique mechanism of cell death in TP53-mutant NSCLC through a complex pathway involving reactive oxygen species (ROS), p38 MAPK signaling, and the NOXA/caspase-3 axis.

The research demonstrated that RG7388 induces both apoptosis and pyroptosis in TP53-mutant NSCLC cell lines, characterized by distinctive morphological changes and molecular mechanisms. Critically, the study identified a novel signaling pathway where ROS triggers p38 MAPK activation and NOXA upregulation, leading to cell death. Immunohistochemical analysis further suggested that the p-p38/NOXA axis could serve as a potential prognostic biomarker for overall survival in NSCLC patients.