Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis
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 (TP53 WT)...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-06-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07770-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850207074167816192 |
|---|---|
| author | Gaoyan Tang Xuelei Cao Jiaqi Chen Fu Hui Na Xu Yiqing Jiang Hongmin Lu Haifeng Xiao Xiuming Liang Mingzhe Ma Yu Qian Dongli Liu Zhenlu Wang Shuzhen Liu Guohua Yu Lei Sun |
| author_facet | Gaoyan Tang Xuelei Cao Jiaqi Chen Fu Hui Na Xu Yiqing Jiang Hongmin Lu Haifeng Xiao Xiuming Liang Mingzhe Ma Yu Qian Dongli Liu Zhenlu Wang Shuzhen Liu Guohua Yu Lei Sun |
| author_sort | Gaoyan Tang |
| collection | DOAJ |
| description | 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 (TP53 WT) NSCLC by triggering the p53/PUMA axis-dependent apoptosis. However, our study uncovered previously unrecognized p53-independent anticancer effects of RG7388 in TP53-mutant (TP53 mutant) 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 TP53 mutant 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 TP53 mutant 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 TP53 mutant 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. |
| format | Article |
| id | doaj-art-59153e594c1942d2b5d5dfcaa3aaa7ba |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-59153e594c1942d2b5d5dfcaa3aaa7ba2025-08-20T02:10:38ZengNature Publishing GroupCell Death and Disease2041-48892025-06-0116111710.1038/s41419-025-07770-2Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axisGaoyan Tang0Xuelei Cao1Jiaqi Chen2Fu Hui3Na Xu4Yiqing Jiang5Hongmin Lu6Haifeng Xiao7Xiuming Liang8Mingzhe Ma9Yu Qian10Dongli Liu11Zhenlu Wang12Shuzhen Liu13Guohua Yu14Lei Sun15Department of Oncology, Weifang People’s Hospital, the First Affiliated Hospital of Shandong Second Medical UniversityDepartment of Clinical Laboratory, Qilu Hospital of Shandong UniversityCancer Prevention and Treatment Center, The Second Hospital of Shandong UniversityDepartment of Oncology, Weifang People’s Hospital, the First Affiliated Hospital of Shandong Second Medical UniversityDepartment of Oncology, Weifang People’s Hospital, the First Affiliated Hospital of Shandong Second Medical UniversityDepartment of Oncology, Weifang People’s Hospital, the First Affiliated Hospital of Shandong Second Medical UniversityDepartment of Oncology, Shanghai Renji Hospital, Shanghai Jiaotong University medical schoolDepartment of Oncology, Weifang People’s Hospital, the First Affiliated Hospital of Shandong Second Medical UniversityDivision for Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska InstitutetDepartment of Gastric Surgery, Fudan University Shanghai Cancer CenterDepartment of thoracic head and neck medical oncology, University of Texas MD Anderson Cancer CenterDepartment of Radiation Oncology, Shanghai General Hospital, Shanghai Jiaotong University medical schoolDepartment of Oncology, Weifang People’s Hospital, the First Affiliated Hospital of Shandong Second Medical UniversityDepartment of Oncology, Weifang People’s Hospital, the First Affiliated Hospital of Shandong Second Medical UniversityDepartment of Oncology, Weifang People’s Hospital, the First Affiliated Hospital of Shandong Second Medical UniversityDepartment of Oncology, Weifang People’s Hospital, the First Affiliated Hospital of Shandong Second Medical UniversityAbstract 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 (TP53 WT) NSCLC by triggering the p53/PUMA axis-dependent apoptosis. However, our study uncovered previously unrecognized p53-independent anticancer effects of RG7388 in TP53-mutant (TP53 mutant) 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 TP53 mutant 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 TP53 mutant 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 TP53 mutant 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.https://doi.org/10.1038/s41419-025-07770-2 |
| spellingShingle | Gaoyan Tang Xuelei Cao Jiaqi Chen Fu Hui Na Xu Yiqing Jiang Hongmin Lu Haifeng Xiao Xiuming Liang Mingzhe Ma Yu Qian Dongli Liu Zhenlu Wang Shuzhen Liu Guohua Yu Lei Sun Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis Cell Death and Disease |
| title | Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis |
| title_full | Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis |
| title_fullStr | Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis |
| title_full_unstemmed | Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis |
| title_short | Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis |
| title_sort | repurposing mdm2 inhibitor rg7388 for tp53 mutant nsclc a p53 independent pyroptotic mechanism via ros p p38 noxa caspase 3 gsdme axis |
| url | https://doi.org/10.1038/s41419-025-07770-2 |
| work_keys_str_mv | AT gaoyantang repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT xueleicao repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT jiaqichen repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT fuhui repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT naxu repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT yiqingjiang repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT hongminlu repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT haifengxiao repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT xiumingliang repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT mingzhema repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT yuqian repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT dongliliu repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT zhenluwang repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT shuzhenliu repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT guohuayu repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis AT leisun repurposingmdm2inhibitorrg7388fortp53mutantnsclcap53independentpyroptoticmechanismviarospp38noxacaspase3gsdmeaxis |