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Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via
Gaoyan Tang1, Xuelei Cao2,3, Jiaqi Chen4
1Department of Oncology, Weifang People's Hospital, the First Affiliated Hospital of Shandong Second Medical University, Weifang, China.
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.
Insights
RG7388 triggers apoptosis and pyroptosis in mutant p53 non-small cell lung cancer (NSCLC) via a novel ROS/p38 MAPK pathway. This discovery offers new therapeutic strategies for targeting NSCLC with mutant p53.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) presents significant treatment challenges due to tumor heterogeneity and resistance.
- MDM2 inhibitor RG7388 shows efficacy in TP53-wild-type NSCLC via p53-dependent apoptosis.
- The anticancer mechanisms of RG7388 in TP53-mutant NSCLC were previously unknown.
Purpose of the Study:
- To elucidate the p53-independent anticancer effects of RG7388 in TP53-mutant NSCLC.
- To identify the molecular pathways mediating RG7388-induced cell death in this context.
- To explore the potential of the identified pathway as a therapeutic target and prognostic biomarker.
Main Methods:
- In silico analyses and biological assays to study RG7388 effects.
- Investigation of reactive oxygen species (ROS) and p38 MAPK signaling.
- Use of ROS scavengers (NAC, Fer-1) and p38 MAPK inhibitor (SB203580).
- Immunohistochemical analysis of NSCLC tissue microarrays and clinical data analysis.
Main Results:
- RG7388 induced NOXA/caspase-3 apoptosis and GSDME-mediated pyroptosis in TP53-mutant NSCLC.
- Reactive oxygen species (ROS) mediated NOXA upregulation and p38 MAPK activation.
- The ROS/phosphorylated p38 MAPK (p-p38)/NOXA/caspase-3 axis was critical for RG7388-induced cell death.
- A positive correlation between p-p38 and NOXA expression was observed in NSCLC tissues.
Conclusions:
- RG7388 exhibits p53-independent anticancer activity in mutant NSCLC through ROS/p-p38-mediated NOXA accumulation, inducing apoptosis and pyroptosis.
- The ROS/p-p38/NOXA/caspase-3 axis represents a novel therapeutic strategy for targeting mutant p53 NSCLC.
- The p-38/NOXA axis shows potential as a prognostic biomarker for NSCLC patient survival.
