bims-p53act 2025-12-28 papers

Blood Adv. 2025 Dec 22. pii: bloodadvances.2025016765. [Epub ahead of print]

Inhibition of NAMPT targets DNA damage response to sensitize alkylating chemotherapy in TP53 mutant mantle cell lymphoma.

Na Li, Yicen Liu, Linna Zhang, Saisai Guo, Zhihao Wu, Yan Xu, Ming Yang, Jixia Kong, Yuxuan Che, Kun Shao, Hong Yang.

TP53-mutant mantle cell lymphoma (MCL) patients face poor chemotherapy response and early progression, requiring novel therapies. We identify NAMPT, the rate-limiting NAD+ salvage enzyme, overexpressed in MCL cell lines and patient tissues, emerges as a therapeutic target. The NAMPT inhibitor KPT-9274 reduced viability and induced apoptosis in MCL cells irrespective of TP53 status. Mechanistic studies reveal a striking dichotomy: in TP53-mutant cells, NAMPT inhibition triggers synthetic lethality through catastrophic DNA damage response (DDR) pathway disruption, while in TP53 wild-type cells, it selectively suppresses B-cell receptor signaling and immune checkpoint activation. This biological divergence translates to clinically actionable synergies-TP53-mutant cells exhibit marked sensitization to alkylating agents and DDR-targeting therapies, whereas TP53 wild-type models show potential for overcoming BTK inhibitor resistance. In vivo studies confirm that NAMPT-based combinations achieve profound tumor regression in TP53-mutant xenografts without exacerbating toxicity. Our findings establish NAMPT as a dual-context therapeutic node, providing a precision medicine framework to circumvent chemoresistance in high-risk MCL. These results advocate for the clinical evaluation of TP53 status-guided NAMPT inhibitor combinations to address this unmet oncologic challenge.

DOI: https://doi.org/10.1182/bloodadvances.2025016765

Curr Oncol. 2025 Dec 03. pii: 684. [Epub ahead of print]32(12):

Breast Cancer Therapy by Small-Molecule Reactivation of Mutant p53.

Simon H Slight, Salman M Hyder.

Tumor suppressor p53 is essential for maintaining DNA stability and preventing cancer. Under normal conditions, the p53 protein is either degraded or bound to a negative regulator, rendering it inactive, but when DNA damage occurs, p53 is activated, causing cell cycle arrest and allowing time for cellular repair. If, however, DNA damage is too severe, the cell undergoes apoptosis and is eliminated. Mutations in the p53 gene are linked to various types of cancer and are present in 30-40% of human breast cancers, leading to loss of tumor suppressor function and uncontrolled tumor growth. Moreover, in triple-negative breast cancer (TNBC), a particularly deadly form of the disease, the incidence of p53 mutations increases to 70-80%. Many p53 mutations occur in the DNA binding domain of the p53 gene, leading to accumulation of mutant p53 (mtp53) within the cell, and tumor development. Converting mtp53 back to its functional wild-type form (wtp53) is consequently a rational approach to preventing or even reversing tumor growth. Mechanisms of action of tumor suppressor p53 are widely discussed elsewhere; hence, we will focus on our own studies, using small molecule activators of mtp53 to combat breast cancer. We will show that specific small molecules, such as PRIMA-1 (p53 reactivation and induction of mass apoptosis), reactivate mtp53 in hormone-dependent human breast cancer cells. Furthermore, we will demonstrate the effectiveness of PRIMA-1 at arresting xenograft growth in an animal model and go on to show that the PRIMA-1 analog APR-246 effectively restores wtp53 tumor suppressor activity in TNBC cells. A brief overview of current clinical trials aimed at reactivating p53 to treat certain cancers is provided. Finally, we discuss the possible use of naturally occurring compounds, which are generally non-toxic, to reactivate mutant p53 and control TNBC progression.

Keywords: PRIMA1; breast cancer; p53; reactivation

DOI: https://doi.org/10.3390/curroncol32120684

South Asian J Cancer. 2025 Jul;14(3): 480-484

Immunohistochemical Expression of p53 in Epithelial Ovarian Carcinoma and Its Correlation with Clinicopathological Parameters.

Farzana Sharmin, Noor-E-Ferdous Noor-E-Ferdous, Latifa Akhter, Khairun Nahar, Towhidul Islam, Jannatul Ferdous.

Introduction: Mutation of p53 is often considered to be associated with high-grade epithelial ovarian cancer that carries a poor prognosis. The purpose of the study was to evaluate the pattern of immunohistochemical expression of p53 in epithelial ovarian carcinoma (EOC) and to find out its correlation with clinicopathological parameters of the disease.
Methods: This observational, cross-sectional study was conducted at the Department of Gynecological Oncology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, from July 2022 to June 2023. A total of 50 women diagnosed with EOCs and scheduled for primary debulking surgery were selected for the study. A semiquantitative histochemical scoring method was employed for p53 nuclear staining, with over 1,000 tumor cells assessed across multiple high-power fields for percentage and intensity of staining. Positive and negative control slides were incorporated during staining procedures to ensure reliability. Statistical analyses included chi-square or Fisher's exact tests for categorical variables, Mann-Whitney tests for nonnormally distributed continuous data, and Spearman's correlation for relationships between various parameters.
Results: Of the total 50 study participants were included, 31 (62%) exhibited p53 mutations, while 19 (38%) showed no such mutations. The presence of p53 mutation was significantly associated with a family history of ovarian cancer ( p = 0.001) and the histological subtypes ( p = 0.046). Regarding histological subtypes, 39 (78%) cases were serous, 9 (18%) cases were mucinous, 1 (2%) case was seromucinous, and 1 (2%) case was of endometrioid variety. Preoperative median CA-125 levels were significantly higher in advanced-stage and high-grade serous ovarian carcinomas compared with early-stage and low-grade cases ( p = 0.016 and p = 0.001, respectively). Although no significant association was found between p53 mutation status and serous carcinoma stage, mutation status was significantly associated with serous carcinoma grade ( p = 0.042), with a moderate positive correlation (Spearman's correlation coefficient, ρ = 0.364).
Conclusion: Our study highlights the significant association of p53 mutations with a family history and histological subtypes of EOC. Elevated preoperative CA-125 levels are associated with advanced-stage and high-grade serous carcinomas. Moreover, higher-grade serous ovarian carcinomas are significantly associated with the presence of p53 mutations, providing valuable insights into pathogenesis and potential treatment strategies.

Keywords: clinicopathological parameters; epithelial ovarian carcinoma (EOC); p53

DOI: https://doi.org/10.1055/s-0045-1809307

Exp Hematol Oncol. 2025 Dec 23. 14(1): 138

Efficacy of melflufen in multiple myeloma with mutated or deleted TP53.

Patients with multiple myeloma bearing a deletion of chromosome 17p (del(17p)), mutation of TP53, or both have poorer prognosis compared to patients without these aberrations. We investigated the activity and mechanism of melflufen (melphalan flufenamide) in myeloma models with wild type TP53 (TP53wt) and complete TP53 deletion (TP53-/-) and assessed the efficacy of melflufen in patients with del(17p) and/or TP53 mutation. Ex vivo data from myeloma plasma cells (PC) showed comparable activity of melflufen in del(17p), TP53-/-, and TP53wt samples. scRNAseq data demonstrated that melflufen sensitive PCs had lower expression of p53 target genes and higher expression of genes associated with DNA damage repair and cell cycle checkpoints. Irrespective of TP53 status, melflufen induced apoptosis, DNA damage, and mitochondrial dysfunction, while only in TP53-/- cells, it led to changes in expression of cell cycle checkpoint and apoptosis genes. Post-hoc analysis of the OCEAN trial melflufen-treated del(17p) patient population also demonstrated favorable progression free survival compared to pomalidomide-treated cohort. Our insights into the molecular mechanisms of melflufen activity in TP53-/- myeloma support its clinical efficacy and application in the del(17p) and TP53-/- patient population.Trial registration NCT03151811, registration 2017-05-09.

Keywords: TP53 mutation; Clinical efficacy; In vitro efficacy; Melflufen; PFS; SoC alkylators; del(17p)

DOI: https://doi.org/10.1186/s40164-025-00729-1

J Cancer Res Ther. 2025 Dec 26.

Inhibition of MDM2 by nutlin-3 decreased pyroptosis but increased apoptosis of lung carcinoma cells under 5-FU chemotherapy.

Tingting Hu, Hongyi Cai, Xiaoyu Duan, Yafei Zhuang.

OBJECTIVES: MDM2 inhibition restores p53 function, and even mutant p53 can induce cancer cell apoptosis. Notably, apoptosis and pyroptosis may interconvert during chemotherapy. This study aimed to explore the role of the MDM2-p53 pathway in the regulation of GSDME-mediated pyroptosis in lung adenocarcinoma.
METHODS: Immunohistochemistry and Western blotting were employed to measure the expression levels of GSDMD, GSDME, cleaved PARP, and MDM2. Nutlin-3, an MDM2 inhibitor, was administered to 5-FU-treated wild-type A549 cells, wild-type HBE cells, GSDME-overexpressing HBE cells, and A549 cells overexpressing p53 codon 72 mutation.
RESULTS: GSDMD and GSDME were expressed in lung adenocarcinoma tissues, adjacent nontumor tissues, and noncancerous lung tissues, whereas only GSDME was expressed in A549 and HBE cells. After chemotherapy, the N-terminal fragment of GSDME was expressed in HBE and A549 cells. GSDME had a significantly lower protein level in HBE cells than in A549 cells ( P = 0.0092). GSDME overexpression markedly increased pyroptosis in A549 ( P = 0.01) and HBE cells ( P = 1.72 × 10 -6 ). Nutlin-3 significantly reduced cell viability and pyroptosis while increasing apoptosis in 5-FU-treated wild-type A549 cells, A549 cells with the p53 codon 72 mutation, and GSDME-overexpressing HBE cells. However, it exerted no significant effects on wild-type HBE cells.
CONCLUSIONS: GSDME-mediated pyroptosis plays a pivotal role in chemotherapy-induced cell death in lung adenocarcinoma. MDM2 inhibition, which switches pyroptosis to apoptosis, can be employed to regulate chemotherapy-induced pyroptosis in lung cancer cells and normal tissue cells.

Keywords: Adenocarcinoma; GSDME; MDM2; cancer-adjacent tissues; non-small cell lung cancer; pyroptosis

DOI: https://doi.org/10.4103/jcrt.jcrt_2060_24