bims-p53act 2026-04-12 papers

bims-p53act

Biomed News

on p53 mutations and anti-cancer therapy response

Issue of 2026–04–12
seven papers selected by
Toni Martínez Bernabé, Universitat de les Illes Balears

Unraveling the role of TP53 mutations in myeloproliferative neoplasms: Molecular mechanisms of leukemic transformation.
p53: from understanding its structure to advances in therapeutic targeting.
Characteristics of p53 and Smad4 immunohistochemistry in pancreatic ductal adenocarcinoma and validation by next-generation sequencing.
Discovery of novel covalent agonists for p53 Y220C through synergistic strategy combining covalent binding and scaffold hopping.
Molecular and Clinicopathologic Features Associated With FOLR1 Expression in Gynecologic Malignancies.
Tamoxifen differentially modulates endometrial hyperplasia via wild-type and mutant p53 regulation of the ALKBH5-REG1A axis.
Celastrol overcomes 5-fluorouracil resistance in osteosarcoma cells through p53-mediated apoptotic pathway modulation and P-glycoprotein inhibition: A comprehensive mechanistic study.

Hemasphere. 2026 Mar;10(3): e70332

Unraveling the role of TP53 mutations in myeloproliferative neoplasms: Molecular mechanisms of leukemic transformation.

Suzana da Silva-Benedito, Paula Sabbo Bernardo, Jean-Edouard Martin, Caroline Marty, Isabelle Plo, Iléana Antony-Debré, Bárbara da Costa Reis Monte-Mór.

TP53 mutations are found in over 50% of tumor types, including myeloproliferative neoplasms (MPNs). MPNs are characterized by a chronic phase, which may progress to secondary acute myeloid leukemia (sAML). Here, we discuss the physiological functions of p53 in hematopoiesis and its deregulation in MPNs. Additionally, we explore the mechanisms underlying TP53 mutations in the leukemic transformation of MPNs, including clonal evolution to multihit status and the role of inflammation and therapy. Finally, recent findings on the clinical impact of multihit TP53 mutations and potential strategies for targeting the p53 pathway in MPNs and sAML are presented.

DOI: https://doi.org/10.1002/hem3.70332
Signal Transduct Target Ther. 2026 Apr 06. pii: 121. [Epub ahead of print]11(1):

p53: from understanding its structure to advances in therapeutic targeting.

Wenhua Wang, Xia Liu, Hengqi Liu, Hassan Abolhassani, Han Yan, Huilai Zhang, Xianhuo Wang.

The tumor suppressor gene TP53 is the most frequently mutated gene in human cancers and has been a popular area of research in the field of oncology. The p53 protein, encoded by the TP53 gene, not only binds to many targeted genes but also regulates apoptosis, autophagy, cell cycle arrest, metabolism, senescence and the tumor immune microenvironment to suppress tumorigenesis. In recent years, an increasing number of new functions of p53 have been discovered, and p53-mediated tumor suppressor functions have been greatly expanded. Mutations in TP53 not only abolish its ability to suppress tumorigenesis but also confer carcinogenic properties to p53-mutant cells. Because of the prevalence of p53 dysfunction in various disease types, p53 has long been considered an attractive target for new anticancer drugs. However, drugs targeting p53 are still under investigation in early clinical trials and have not been approved for clinical use. This finding is consistent with the speculation that p53 is widely regarded as "undruggable." Surprisingly, several novel therapeutic approaches targeting p53, including MDM2/4 antagonists, compounds that target specific p53 mutants or restore the wild-type function of the mutated p53 protein, p53-based genetic therapies and p53-based tumor immunotherapy, have been developed in recent years. Here, we present a review of the structure, inactivation, and roles of p53 in diseases. In addition, this review discusses the efforts to target diseases associated with p53 dysfunction and the challenges encountered in the clinical development of these approaches.

DOI: https://doi.org/10.1038/s41392-025-02549-5
Histol Histopathol. 2026 Apr 06. 25072

Characteristics of p53 and Smad4 immunohistochemistry in pancreatic ductal adenocarcinoma and validation by next-generation sequencing.

Ziqi Zhao, Juan Du, Wenyang Guo, Lingchao Li, Congrong Liu, Limei Guo.

BACKGROUND: Mutations in four major driver genes-KRAS, CDKN2A, TP53, and SMAD4-are central to the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) and critically inform diagnosis, therapeutic decision-making, and prognostic assessment. Although next-generation sequencing (NGS) is widely regarded as the gold standard for detecting these mutations, its clinical application is often limited by suboptimal analytical efficiency and substantial economic cost. Among these genes, immunohistochemical (IHC) staining for the proteins encoded by TP53 and SMAD4 has been extensively adopted in routine pathology practice. However, standardized IHC pattern classification schemes and rigorous validation of their predictive accuracy for underlying genomic alterations remain lacking in PDAC.
METHODS: We retrospectively enrolled 63 PDAC patients and systematically characterized the typical IHC expression patterns of p53 and Smad4. Targeted NGS was subsequently performed on all available tumor specimens, and the resulting mutational profiles were correlated with corresponding IHC findings. Diagnostic performance including sensitivity, specificity and accuracy of p53 IHC for predicting TP53 mutations and of Smad4 IHC for predicting SMAD4 mutations was rigorously evaluated.
RESULTS: Among the four canonical driver genes, co-occurring double- or triple-gene mutations were prevalent; within TP53 and SMAD4, missense mutations constituted the most frequent variant type. Using NGS as the reference standard, we validated the diagnostic utility of a three-tiered p53 IHC classification system, particularly in fine-needle biopsy (FNB) specimens. Furthermore, we proposed a novel, refined Smad4 IHC pattern classification that incorporates an "intermediate" category, thereby expanding upon conventional binary interpretation. This new scheme achieved markedly improved mutation prediction accuracy (0.76) compared with traditional approaches (0.57).
CONCLUSION: Our study highlights the complementary diagnostic value of p53 and Smad4 IHC relative to molecular testing in PDAC, especially when tissue is limited, as commonly encountered in FNB specimens. The newly established Smad4 IHC classification system, which integrates an intermediate expression category into the conventional two-tier framework, demonstrates superior clinical utility and enhances predictive accuracy for SMAD4 genomic alterations.

DOI: https://doi.org/10.14670/HH-25-072
Eur J Med Chem. 2026 Mar 31. pii: S0223-5234(26)00246-1. [Epub ahead of print]311 118801

Discovery of novel covalent agonists for p53 Y220C through synergistic strategy combining covalent binding and scaffold hopping.

Linquan Li, Jingyi Meng, Fengqian Xu, Kang Wang, Xiaoqian Wang, Xi Gu, Haiwei Shen, Sulin Zhang, Zhili Zuo.

  The Y220C mutation represents one of the most frequent mutational variants in p53. This mutant impairs p53-mediated tumor suppression and heightens oncogenic risk. Consequently, activating the antitumor function of p53 mutants emerges as a promising therapeutic strategy for diverse malignancies. Herein, we report a strategic concept targeting the shallow neomorphic pocket created by the p53 Y220C mutant with covalent small molecules. Utilizing scaffold hopping, we identified the privileged pyrrolopyrimidine scaffold and subsequently designed high-potency compounds through covalent warhead replacement and systematic structural optimization. The protein thermal shift assay confirmed enhanced thermal stabilization of p53 Y220C. Several compounds restored its DNA-binding capacity. Among them, LLQ-45 showed selective activity against p53 Y220C-mutant tumor cells, inhibiting their proliferation and markedly upregulating CDKN1A expression in a dose-dependent manner. These results demonstrate that LLQ-45 activates the antitumor function of p53 Y220C via covalent modification, thereby suppressing tumor cell growth. This study provides a framework for targeting neomorphic pockets and advances targeted cancer therapies.

Keywords:  Activator; Drug design; Structural modification; Synthesis; p53 Y220C

DOI:  https://doi.org/10.1016/j.ejmech.2026.118801
Int J Gynecol Pathol. 2026 Apr 07.

Molecular and Clinicopathologic Features Associated With FOLR1 Expression in Gynecologic Malignancies.

Rachelle P Mendoza, Marie C Smithgall, Xiaowei Chen, Xiaolin Liu-Jarin, Adela Cimic.

  Folate receptor 1 (FOLR1) has recently become a well-accepted therapeutic target in advanced-stage cancers. In this study, the prevalence of FOLR1 expression across all types of gynecologic tumors was investigated and correlated with selected clinicopathologic features. A total of 306 gynecologic tumors from 304 patients were evaluated for FOLR1 expression by immunohistochemistry (IHC). A positive FOLR1 is defined as ≥75% of viable tumor cells with moderate to strong membrane staining. Of 306 tumors, 31 (10.1%) had positive FOLR1 tests; a large majority of these FOLR1-positive tumors were HGSCs (64.5%), followed by uterine serous carcinoma, poorly differentiated/high-grade carcinoma, ovarian endometrioid carcinoma, ovarian mixed carcinoma, ovarian low-grade serous carcinoma, and serous borderline tumor with cribriform and micropapillary features. FOLR1 overexpression correlated with positive PD-L1 expression (P=0.012), intact mismatch repair protein (MMR) expression (P=0.024), and positive ER expression (P=0.040). In endometrial tumors, positive FOLR1 expression was associated with poor histologic grade (P=0.019), larger tumor size (P=0.048), mutant p53 expression (P<0.001), and lower PR expression (P=0.015). Endometrial tumors with FOLR1 overexpression had a significantly higher rate of TP53 mutations (P=0.013), while all endometrial tumors with PTEN alterations were negative for FOLR1 (P=0.037). Overall, FOLR1 overexpression was associated with poor prognostic factors, such as advanced clinical stage, increased recurrence rate, higher pathologic T and N stage, poor histologic grade, larger tumor size, lymphovascular invasion, uterine serosa involvement, and shorter progression-free survival.

Keywords:  FOLR1 expression; Gynecologic malignancy; TP53 mutation

DOI:  https://doi.org/10.1097/PGP.0000000000001176
Front Oncol. 2026 ;16 1784356

Tamoxifen differentially modulates endometrial hyperplasia via wild-type and mutant p53 regulation of the ALKBH5-REG1A axis.

Rencheng Wang, Jianhua Ji, Lei Liu.

   Introduction: Tamoxifen is a cornerstone of endocrine therapy for estrogen receptor-positive breast cancer; however, its partial estrogen agonist activity in the endometrium predisposes patients to hyperplasia and, in some cases, malignant transformation. The molecular mechanisms underlying this tissue-specific adverse effect remain incompletely understood.
Methods: We employed immortalized human endometrial epithelial cells to investigate the role of p53 in tamoxifen-induced proliferation. Cells were genetically manipulated to express wild-type (WT) or mutant p53 (R248Q), and ALKBH5 or REG1A was silenced or overexpressed using lentiviral constructs. A comprehensive set of molecular techniques-including quantitative reverse transcription PCR (qRT-PCR), Western blotting, chromatin immunoprecipitation (ChIP), luciferase reporter assays, methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), and functional proliferation assays (CCK-8 and colony formation)-was applied to dissect transcriptional and post-transcriptional regulatory mechanisms.
Results: Tamoxifen promoted the recruitment of WT p53 to the ALKBH5 promoter, transcriptionally activating this m6A RNA demethylase. ALKBH5 subsequently erased m6A modifications from REG1A mRNA, preventing YTHDF2-mediated decay and thereby stabilizing REG1A expression. Elevated REG1A protein functioned as a negative feedback regulator, attenuating tamoxifen-induced proliferation. In stark contrast, the p53 R248Q mutant, despite retaining promoter-binding capacity, suppressed ALKBH5 transcription-potentially through altered cofactor recruitment-leading to increased m6A methylation of REG1A transcripts, enhanced YTHDF2-dependent degradation, and consequently, exaggerated cellular proliferation. Loss-of-function and genetic rescue experiments established that ALKBH5 is both necessary and sufficient to regulate REG1A mRNA stability, and that REG1A serves as the critical downstream effector mediating proliferative restraint under tamoxifen treatment.
Conclusions: Tamoxifen's anti-proliferative effects in endometrial epithelial cells are critically dependent on WT p53, which coordinates a protective epitranscriptomic regulatory axis. In contrast, mutant p53 disrupts this checkpoint and redirects tamoxifen signaling toward hyperproliferation. These findings establish a mechanistic link between hormonal signaling, p53 allelic status, and m6A-dependent post-transcriptional regulation. Although further in vivo validation is required, disruption of the ALKBH5-REG1A axis may contribute to heterogeneous endometrial responses to tamoxifen, thereby providing a conceptual framework for biomarker-oriented investigation.

Keywords:  ALKBH5; REG1A; endometrial hyperplasia; p53; tamoxifen

DOI:  https://doi.org/10.3389/fonc.2026.1784356
Bioimpacts. 2026 ;16 32819

Celastrol overcomes 5-fluorouracil resistance in osteosarcoma cells through p53-mediated apoptotic pathway modulation and P-glycoprotein inhibition: A comprehensive mechanistic study.

Mohammad Ebrahimnezhad, Amir Valizadeh, Bahman Yousefi, Dariush Shanehbandi.

   Introduction: Osteosarcoma, a prevalent malignant bone tumor in children and adolescents, is hindered by chemoresistance, particularly to 5-fluorouracil (5-FU), driven by mechanisms such as P-glycoprotein (P-gp) overexpression and altered p53 signaling. Celastrol, a triterpenoid, exhibits anti-tumor properties, but its potential to overcome 5-FU resistance in osteosarcoma remains underexplored.
Methods: We investigated the synergistic effects of celastrol and 5-FU in human osteosarcoma cell lines with varying p53 statuses (U-2OS, wild-type; SaOS-2, p53-null; HOS, mutant p53) using MTT assays for cytotoxicity, Chou-Talalay method for synergy, and Cell Death Detection ELISA for apoptosis. Gene expression (p53, Bax, Bcl-2, caspase-9) was quantified via qRT-PCR, P-gp levels by Western blot, and P-gp efflux activity by Rhodamine 123 assays. Non-malignant hFOB 1.19 cells served as controls.
Results: Celastrol and 5-FU exhibited potent cytotoxicity, with combination therapy reducing IC₅₀ values 3.7- to 11.9-fold across cell lines, showing strong synergy. The combination significantly enhanced apoptosis and modulated p53-dependent (U-2OS) and -independent (SaOS-2, HOS) pathways, upregulating Bax and caspase-9 while downregulating Bcl-2. Celastrol reduced P-gp expression and increased intracellular drug accumulation, comparable to verapamil.
Conclusion: Celastrol synergizes with 5-FU to overcome chemoresistance in osteosarcoma by enhancing p53-mediated and -independent apoptosis and inhibiting P-gp-mediated drug efflux. These findings suggest a promising low-toxicity therapeutic strategy, warranting further in vivo and clinical investigations.

Keywords:  5-Fluorouracil; Apoptosis; Celastrol; Chemoresistance; Osteosarcoma; P-gp

DOI:  https://doi.org/10.34172/bi.32819