bims-midomi 2025-06-22 papers

bims-midomi

Biomed News

on MDM2 and mitochondria

Issue of 2025–06–22
six papers selected by
Gavin McStay, Liverpool John Moores University

p53 in colorectal cancer: from a master player to a privileged therapy target.
Bypassing the guardian: regulated cell death pathways in p53-mutant cancers.
Repurposing MDM2 inhibitor RG7388 for TP53-mutant NSCLC: a p53-independent pyroptotic mechanism via ROS/p-p38/NOXA/caspase-3/GSDME axis.
The TP53 tumor suppressor gene: From molecular biology to clinical investigations.
Mechanistic Insights of a p53-Targeting Small Molecule.
Resolving spatial subclonal genomic heterogeneity of loss of heterozygosity and extrachromosomal DNA in gliomas.

J Transl Med. 2025 Jun 19. 23(1): 684

p53 in colorectal cancer: from a master player to a privileged therapy target.

Sicheng Yan, Fuyuan Zhan, Yuxuan He, Yuehong Zhu, Zhihong Ma.

  Colorectal cancer (CRC) is the third most prevalent malignancy and the second leading cause of cancer-related mortality worldwide. The pathogenesis of CRC primarily stems from the gradual accumulation of genetic mutations, which drive oncogene (e.g., KRAS) activation and tumor suppressor gene (e.g., TP53) inactivation. Loss of genetic stability facilitates the conversion of proto-oncogenes into active oncogenes and the functional impairment of tumor suppressors, collectively propelling CRC progression. The tumor suppressor protein p53, a transcription factor, induces cell cycle arrest, apoptosis, and DNA damage repair under cellular stress, and prevents cancer development by regulating various cellular responses. However, in CRC pathogenesis, TP53 mutations (detected in ~ 74% of cases) subvert these protective mechanisms through dual mechanisms: (i) dominant-negative suppression of wild-type p53 (wt-p53) function, and (ii) acquisition of neomorphic pro-tumorigenic activities, termed gain-of-function (GOF) mutations. New evidence from laboratory and clinical trials shows that some new therapeutic strategies have the potential to treat CRC by reactivating and restoring p53 function, depleting p53 mutants, or targeting p53 with immunotherapy. In this review, we summarize the function of p53 and characterize its mutation in CRC, emphasizing the influence of p53 mutation in the pathogenesis of CRC. In addition, we also describe the current therapeutic strategies for targeting p53 mutants in CRC.

Keywords:   TP53 ; Colorectal cancer; GOF; Mutant p53; Wild-type p53; p53

DOI:  https://doi.org/10.1186/s12967-025-06566-4
Cell Mol Biol Lett. 2025 Jun 14. 30(1): 68

Bypassing the guardian: regulated cell death pathways in p53-mutant cancers.

Jonathan Y Chung, Bruce A Knutson.

  Approximately half of all cancers bear mutations in the tumor suppressor p53. Despite decades of research studying p53 function, treatment of p53-mutant cancers remains challenging owing to the effects of p53 mutations on many complex and interrelated signaling networks that promote tumor metastasis and chemoresistance. Mutations in p53 promote tumor survival by dysregulating cellular homeostasis and preventing activation of regulated cell death (RCD) pathways, which normally promote organismal health by eliminating dysregulated cells. Activation of RCD is a hallmark of effective cancer therapies, and p53-mutant cancers may be particularly susceptible to activation of certain RCD pathways. In this review, we discuss four RCD pathways that are the targets of emerging cancer therapeutics to treat p53-mutant cancers. These RCD pathways include E2F1-dependent apoptosis, necroptosis, mitochondrial permeability transition-driven necrosis, and ferroptosis. We discuss mechanisms of RCD activation, effects of p53 mutation on RCD activation, and current pharmaceutical strategies for RCD activation in p53-mutant cancers.

Keywords:  Apoptosis; Cancer; Ferroptosis; Metastasis; Necroptosis; P53; Reactive oxygen species

DOI:  https://doi.org/10.1186/s11658-025-00751-5
Cell Death Dis. 2025 Jun 17. 16(1): 452

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

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.

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.

DOI: https://doi.org/10.1038/s41419-025-07770-2
J Intern Med. 2025 Jun 16.

The TP53 tumor suppressor gene: From molecular biology to clinical investigations.

Panagiotis Baliakas, Thierry Soussi.

  Extensively studied over the past four decades, the TP53 gene has emerged as a pivotal watchman in cellular defense and a key factor in cancer biology. TP53 is the most frequently mutated gene in human malignancies, 50% of which carry alterations to it. Initially, the functions of p53 were thought to be restricted to cell-cycle arrest and apoptosis. With time, however, a growing number of functions have been discovered, illustrating p53's role as a master switch between any cellular stress and cellular or multicellular responses that contribute to its anti-tumor activity. Indeed, the peculiar landscape of TP53 mutations and its high heterogeneity are linked both to the structure of the protein and its ubiquitous function in regulating cellular homeostasis. Mutations in p53 are associated with poor response to therapy and shorter survival in most cancer types, and the diagnosis of p53 mutations is currently used to improve case management in some types of leukemia and lymphoma. Although TP53 has been defined as a tumor suppressor gene, overexpressed mutated p53 variants found in human tumors are defined as dominant oncogenes with a potential gain of function, which makes the gene a very attractive target for developing new cancer treatments. Beyond its role in cancer, our review also highlights TP53's significance in non-neoplastic conditions, such as bone marrow failure syndromes and certain developmental disorders, where chronic p53 activation plays a crucial role in cellular stress responses, demonstrating its broader biological importance.

Keywords:  TP53; cancer; developmental syndrome; patient management; tumor suppressor gene

DOI:  https://doi.org/10.1111/joim.20106
ACS Pharmacol Transl Sci. 2025 Jun 13. 8(6): 1726-1740

Mechanistic Insights of a p53-Targeting Small Molecule.

Ricardo J F Ferreira, Valentina Barcherini, Catarina Roma-Rodrigues, Miriama Sikorová, Lucília Saraiva, Ana P Leandro, Pedro V Baptista, Alexandra R Fernandes, Alexandra M M Antunes, Maria M M Santos.

  Restoring the p53 pathway, particularly by reactivating wild-type (wt) or mutant (mut) p53, is considered a promising approach for cancer treatment. Previously, we identified the tryptophanol-derived oxazoloisoindolinone family as a new scaffold for obtaining wt and mut p53 reactivators. Herein, we report a detailed study on the pharmacokinetic profile and the mechanism of action of RVJB59, an (R)-tryptophanol-derived oxazoloisoindolinone that exhibits six times higher activity and increased selectivity for HCT116 cells with p53 compared to our initial hit, SLMP53-1. In vitro metabolic degradation studies in human liver microsomes and rat liver S9 fractions, assessed by LC/HRMS/MS, showed that RVJB59 is a low-clearance compound. The three main metabolites identified were synthesized, and their antiproliferative activity was evaluated against HCT116 colon cancer cells with and without p53, showing a loss of activity when compared to RVJB59. DSF studies showed that RVJB59 enhances the thermostability of the wt and R273H p53 DNA-binding domain, with this mutant showing melting curves with two melting transitions, distinct from those obtained for the wild-type. The ability of RVJB59 to undergo covalent binding via nucleophilic aromatic substitution was assessed by HRMS/MS, using glutathione and wt p53 as case studies. These assays showed low reactivity toward glutathione and remarkable selectivity toward Cys141 of wt p53. The effect of RVJB59 was also evaluated in 3D spheroids of HCT116 cells and in vivo using chicken embryos, with RVJB59 reducing 3D tumor spheroid growth and exhibiting antiangiogenic potential. This study provides additional evidence of the potential of RVJB59 in activating p53.

Keywords:  cancer; cysteine; isoindolinones; p53; protein modification

DOI:  https://doi.org/10.1021/acsptsci.5c00110
Nat Commun. 2025 Jun 13. 16(1): 5290

Resolving spatial subclonal genomic heterogeneity of loss of heterozygosity and extrachromosomal DNA in gliomas.

Michelle G Webb, Frances Chow, Carmel G McCullough, Bohan Zhang, John J Y Lee, Rania Bassiouni, Norman E Garrett, Kyle Hurth, John D Carpten, Gabriel Zada, David W Craig.

Mapping the spatial organization of DNA-level somatic copy number changes in tumors can provide insight to understanding higher-level molecular and cellular processes that drive pathogenesis. We describe an integrated framework of spatial transcriptomics, tumor/normal DNA sequencing, and bulk RNA sequencing to identify shared and distinct characteristics of an initial cohort of eleven gliomas of varied pathology and a replication cohort of six high-grade glioblastomas. We identify focally amplified extrachromosomal DNA (ecDNA) in four of the eleven initial gliomas, with subclonal tumor heterogeneity in two EGFR-amplified grade IV glioblastomas. In a TP53-mutated glioblastoma, we detect a subclone with EGFR amplification on ecDNA coupled to chromosome 17 loss of heterozygosity. To validate subclonal somatic aneuploidy and copy number alterations associated with ecDNA double minutes, we examine the replication cohort, identifying MDM2/MDM4 ecDNA subclones in two glioblastomas. The spatial heterogeneity of EGFR and p53 inactivation underscores the role of ecDNA in enabling rapid oncogene amplification and enhancing tumor adaptability under selective pressure.

DOI: https://doi.org/10.1038/s41467-025-59805-z