bims-p53act 2026-01-04 papers

bims-p53act

Biomed News

on p53 mutations and anti-cancer therapy response

Issue of 2026–01–04
eight papers selected by
Toni Martínez Bernabé, Universitat de les Illes Balears

High-Throughput RNA Interference Screen Targeting Synthetic-Lethal Gain-of-Function of Oncogenic Mutant TP53 in Triple-Negative Breast Cancer.
Capturing the Variations in Mutant p53-Driven Regulatory Networks in Breast Cancer Subtypes, Its Clinical Relevance and a Novel Association With Androgen Receptor and EMT.
TP53 Splice Mutations Have Tumour-Independent Effects on Genomic Stability and Prognosis: An In Silico Study.
Pandora's Box of AML: How TP53 Mutations Defy Therapy and Hint at New Hope.
Mutant p53 promotes clonal hematopoiesis through generating a chronic inflammatory microenvironment.
TP53 Genotype-Dependent Cellular Responses to DVDMS-Sonodynamic Therapy in Oral Squamous Cell Carcinoma.
Secondary Genetic Events and Their Relationship to TP53 Mutation in Mantle Cell Lymphoma: A Sub-Study from the FIL_MANTLE-FIRST BIO on Behalf of Fondazione Italiana Linfomi (FIL).
Can TP53, TMB and TME Expand the Immunotherapy Benefit in Metastatic Colorectal Cancer?

Methods Mol Biol. 2026 ;2983 371-378

High-Throughput RNA Interference Screen Targeting Synthetic-Lethal Gain-of-Function of Oncogenic Mutant TP53 in Triple-Negative Breast Cancer.

Susumu Rokudai.

  TNBC is an aggressive and metastatic subtype of breast cancer in which the TP53 mutation occurs frequently and is associated with particularly poor outcomes. Mutations in TP53 can disrupt the intrinsic function of the tumor suppressor as well as acquire oncogenic gain-of-function (GOF) activities. However, little is known about its oncogenic GOF mediators and functions. Targeted therapy for TNBC patients is thus one of the most urgent needs in breast cancer therapeutics, and identifying genes that have synthetic lethal interactions with mutant TP53 may be a promising approach. Sequential analysis of RNA-seq followed by high-throughput RNA interference screening (HTS-RNAi screening), as an intrinsic cellular mechanism for the identification of genes with synthetic lethality of mutant TP53, is a promising strategy for the treatment of mutant TP53 in TNBC and determining its impact on tumorigenesis.

Keywords:  Adenosine receptor; High-throughput RNA interference screens (HTS-RNAi screens); Molecular-targeting cancer therapy; Mutant TP53; Triple-negative breast cancer (TNBC)

DOI:  https://doi.org/10.1007/978-1-0716-4901-5_30
IUBMB Life. 2026 Jan;78(1): e70081

Capturing the Variations in Mutant p53-Driven Regulatory Networks in Breast Cancer Subtypes, Its Clinical Relevance and a Novel Association With Androgen Receptor and EMT.

Aastha Singh, Rahul Gupta, Ritu Kulshreshtha.

  The tumour suppressor TP53 is frequently mutated in breast cancer and drives poor outcomes. The impact of mutant p53 (mutp53) on subtype-specific gene and non-coding RNA networks, and their clinical significance, remains largely underexplored. Here, using TCGA-BRCA data, we have delineated subtype-specific mRNA, lncRNA, and microRNA signatures, pathways, co-expression/interaction networks, and prognosis associated with hotspot mutp53 or wildtype p53 tumours. Our study shows that mutp53 deregulates the genes related to EMT, chemoresistance, and prognosis in a subtype-specific manner. The EMT-associated signature was able to stratify HER2 and Basal patients by their p53 status. Construction of lncRNA-mRNA-miRNA interaction networks led to the identification of various feedback loops and hub genes with prognostic relevance that possess binding sites for p53 and EMT-TFs within their promoters. In the basal mutp53 tumours, we found Androgen Receptor (AR) to be a downregulated EMT-associated gene, with its higher levels linked to a better prognosis. We validated that mutp53 breast cancer cell lines show reduced levels of AR and its predicted transcriptional target, miR-196a-5p. Overexpression of WTp53 resulted in the upregulation of AR and miR-196a-5p, while mutp53 (R175H) suppressed their expression. Basal mutp53 tumours with low AR displayed higher EMT scores. Enforced expression of AR led to suppression of mesenchymal markers in basal cell lines. Overall, we have identified novel prognostically relevant RNA signatures and networks that may serve as attractive therapeutic targets in mutp53 breast cancer patients in a subtype-specific manner. Additionally, we have discovered a novel AR:mutp53 association that may be implicated in EMT and chemoresistance.

Keywords:  EMT; TCGA; breast cancer; lncRNAs; miRNAs; p53

DOI:  https://doi.org/10.1002/iub.70081
Int J Mol Sci. 2025 Dec 16. pii: 12080. [Epub ahead of print]26(24):

TP53 Splice Mutations Have Tumour-Independent Effects on Genomic Stability and Prognosis: An In Silico Study.

Apeksha Arun Bhandarkar, Noah Ethan Kelly-Foleni, Debina Sarkar, Aaron Jeffs, Tania Slatter, Antony Braithwaite, Sunali Mehta.

  The tumour suppressor TP53 (tumor protein p53) is a master regulator of cell cycle, DNA repair, and apoptosis, and its mutation is a hallmark of cancer, with individual mutations exerting distinct effects on tumour biology. Despite accounting for ~7% of all TP53 variants, splice site mutations remain the least studied class, and their functional and clinical consequences are poorly understood. We analyzed 25,058 TP53 variants (18,562 somatic; 6496 germline) to characterize the frequency, molecular impact, transcriptional effects, genomic instability, and clinical outcomes of splice mutations. These alterations showed distinct distributions and substitution patterns between germline and somatic contexts and were frequently associated with copy number alterations, reduced TP53 mRNA, and variable protein expression. Transcriptomic profiling identified two transcriptional phenotypes: one with global suppression of canonical p53 target genes and another with mixed activation and repression independent of tumour type. Genomic instability was elevated in a subset of splice-mutant tumours, correlating with increased relapse risk, while other splice mutations showed lower instability but divergent clinical outcomes, including unexpectedly poor prognoses. Our findings fill a critical knowledge gap, defining the biological and clinical spectrum of TP53 splice site mutations and highlighting their potential as prognostic biomarkers and therapeutic targets in precision oncology.

Keywords:  isoforms; mutation; p53; splice

DOI:  https://doi.org/10.3390/ijms262412080
Biomedicines. 2025 Dec 08. pii: 3007. [Epub ahead of print]13(12):

Pandora's Box of AML: How TP53 Mutations Defy Therapy and Hint at New Hope.

Elyse A Olesinski, Shruti Bhatt.

  TP53 mutations are among the worst prognostic factors in acute myeloid leukemia (AML), with affected patients facing relapse-free survival of just five-to-six months compared to TP53 wild-type patients. A major barrier to improving outcomes lies in the dearth of effective therapies, as TP53 mutant patients remain refractory to conventional cytotoxic chemotherapies, targeted therapies, and even allogeneic stem cell transplantation. In this review, we first summarize current clinical strategies and the major setbacks of p53 activators, MDM2/X regulators, and immunotherapy, highlighting the disconnect between promising pre-clinical studies and limited durable clinical responses. We next discuss the mechanisms of therapy resistance in TP53 mutant AML, with specific emphasis on dysfunction in the mitochondrial apoptotic pathway and clonal evolution of TP53 mutant hematopoietic stem cells. We then outline a roadmap for developing tailored therapies that may finally redefine prognosis for this high-risk patient population, including apoptotic activators, cell-cycle modulators, and immune- and metabolic-based therapies. We lastly call attention to new biomarker-driven approaches that can improve patient stratification and optimize identification of responders. By connecting mechanistic understanding with translational insights, this review underscores both the formidable challenges and the emerging opportunities in TP53 mutant AML.

Keywords:  AML; TP53 mutations; therapy resistance

DOI:  https://doi.org/10.3390/biomedicines13123007
J Clin Invest. 2025 Dec 30. pii: e184285. [Epub ahead of print]

Mutant p53 promotes clonal hematopoiesis through generating a chronic inflammatory microenvironment.

Sisi Chen, Sergio Barajas, Sasidhar Vemula, Yuxia Yang, Ed Simpson, Hongyu Gao, Rudong Li, Farzaneh Behzadnia, Sarah C Nabinger, David A Schmitz, Hongxia Chen, Wenjie Cai, Shiyu Xiao, Ruyue Luo, Mohammed Abdullahel Amin, Maegan L Capitano, James P Ropa, Aidan Fahey, Shuyi Zhou, Tiffany M Mays, Magdalena Sotelo, Hao Pan, Sophie K Hu, Sophia Veranga, Moiez Ali, Maria Shumilina, Reuben Kapur, Kehan Ren, Yuzhi Jia, Huiping Liu, Irum Khan, Yasmin Abaza, Jessica K Altman, Elizabeth A Eklund, Lucy A Godley, Christine R Zhang, Peng Ji, Seth L Masters, Ben A Croker, H Scott Boswell, George E Sandusky, Zhonghua Gao, Lindsey D Mayo, Sharon A Savage, Stephanie Halene, Yali Dou, Leonidas C Platanias, Madina Sukhanova, Yunlong Liu, Omar Abdel-Wahab, Yan Liu.

  Aged individuals with somatic TP53 mutations manifest clonal hematopoiesis (CH) and are at high risk of developing myeloid neoplasms. However, the underlying mechanisms are not fully understood. Here we show that inflammatory stress confers a competitive advantage to p53 mutant hematopoietic stem and progenitor cells (HSPCs) by activating the NLRP1 inflammasome and increasing the secretion of pro-inflammatory cytokines such as IL-1β, inhibiting wild type (WT) HSPC fitness in a paracrine fashion. During aging, mutant p53 dysregulates pre-mRNA splicing in HSPCs, leading to enhanced NF-κB activation and increased secretion of IL-1β and IL-6, thereby generating a chronic inflammatory bone marrow microenvironment. Furthermore, blocking IL-1β with IL-1β neutralizing antibody or inhibiting IL-1β secretion using gasdermin D (GSDMD) inhibitor decreases the fitness of p53 mutant HSPCs. Thus, our findings uncover an important role for mutant p53 in regulating inflammatory signaling in CH and suggest that curbing inflammation may prevent the progression of TP53-mutant clonal hematopoiesis to myeloid neoplasms.

Keywords:  Cytokines; Hematology; Hematopoietic stem cells; Inflammation; NF-kappaB

DOI:  https://doi.org/10.1172/JCI184285
Ultrasound Med Biol. 2025 Dec 27. pii: S0301-5629(25)00674-X. [Epub ahead of print]

TP53 Genotype-Dependent Cellular Responses to DVDMS-Sonodynamic Therapy in Oral Squamous Cell Carcinoma.

Guo-Gang Dong, Pin-Xiu Pan, Feng-Ting Zhang, Xi-Mei Zhang, Fu-Yu Yang, Li-Min Jia, Wei-Han Zhang, Yan-Hong Lv.

   OBJECTIVE: This study aimed to assess the inhibitory effects and underlying mechanisms of sonodynamic therapy (SDT) mediated by the novel sonosensitizer sinoporphyrin sodium (DVDMS) in oral squamous cell carcinoma (OSCC) cells exhibiting distinct TP53 genotypes.
METHODS: Cytotoxicity, intracellular uptake and localization of DVDMS, reactive oxygen species (ROS) levels, apoptosis and autophagy were assessed in two OSCC cell lines (SAS and HSC-3). Expression levels of p53, Bax, Bcl-2 and LC3B proteins were analyzed. The p53 inhibitor pifithrin-α (PFT-α) was utilized to determine its modulatory effects on SDT-induced cellular responses in SAS cells.
RESULTS: DVDMS-mediated SDT significantly inhibited cell proliferation in both SAS and HSC-3 lines. DVDMS predominantly accumulated in the mitochondria, with higher colocalization observed in SAS cells. SDT induced a marked elevation in intracellular ROS and mitochondrial apoptosis, particularly in SAS cells. After 2 h of SDT, there was a significant decrease in autophagic activity in SAS cells, whereas an increase was noted in HSC-3 cells. In SAS cells, SDT resulted in significant upregulation and nucleocytoplasmic translocation of p53 protein. Treatment with PFT-α partially attenuated apoptosis, reversed autophagy inhibition and suppressed p53 translocation in SAS cells.
CONCLUSION: DVDMS-mediated SDT elicited greater cytotoxic responses in OSCC cells harboring wild-type TP53 (SAS) compared to mutant TP53 (HSC-3) cells. The therapy induced mitochondrial apoptosis and modulated autophagy in both cell lines, with more pronounced responses observed in wild-type TP53 cells. These findings suggest that p53 plays a critical regulatory role in mediating SDT-induced mitochondrial apoptosis and autophagy under DVDMS sensitization in OSCC.

Keywords:  HSC-3 cells; Oral squamous cell carcinoma; SAS cells; Sinoporphyrin sodium; Sonodynamic therapy; p53

DOI:  https://doi.org/10.1016/j.ultrasmedbio.2025.11.011
Cancers (Basel). 2025 Dec 17. pii: 4027. [Epub ahead of print]17(24):

Secondary Genetic Events and Their Relationship to TP53 Mutation in Mantle Cell Lymphoma: A Sub-Study from the FIL_MANTLE-FIRST BIO on Behalf of Fondazione Italiana Linfomi (FIL).

Maria Elena Carazzolo, Francesca Maria Quaglia, Antonino Aparo, Alessia Moioli, Alice Parisi, Riccardo Moia, Francesco Piazza, Alessandro Re, Maria Chiara Tisi, Luca Nassi, Pietro Bulian, Alessia Castellino, Vittorio Ruggero Zilioli, Piero Maria Stefani, Alberto Fabbri, Elisa Lucchini, Annalisa Arcari, Luisa Lorenzi, Barbara Famengo, Maurilio Ponzoni, Angela Ferrari, Simone Ragaini, Jacopo Olivieri, Vittoria Salaorni, Simona Gambino, Marilisa Galasso, Maria Teresa Scupoli, Carlo Visco.

  Background: Mantle Cell Lymphoma (MCL) is an aggressive malignancy with variable clinical behavior, largely reflecting the underlying molecular heterogeneity. The genomic landscape of MCL encompasses gene mutations with strong prognostic implications and secondary genetic events, which are also implicated in the pathogenesis and prognosis of the disease. Methods: We evaluated the diagnostic samples of 73 patients with relapsed/refractory MCL that were enrolled in the Fondazione Italiana Linfomi Mantle First-BIO study. All patients had available data for correlating CNVs with the presence of TP53 mutation. Time to first relapse or progression of disease (POD) was used as the primary outcome measure. Results: We identified CNVs associated with MCL, with Del 9p21.3 (CDKN2A) being the strongest predictor of shorter time to POD (p = 0.01), independently of TP53 mutation in multivariable analysis. Unsupervised clustering identified molecularly defined clusters that were associated with significantly different times to POD (p = 0.01). Pairwise log-rank tests confirmed TP53 mutated vs. wild-type (WT) as the strongest prognostic factor, with cluster assessment improving the prognostic predictivity among patients: clusters TP53-mut vs. TP53-WT, p = 0.001, HR = 3.92; and p = 0.014, HR = 2.23, respectively. In conclusion, CNV-based molecular clusters might represent a novel approach to identify patients at higher risk of treatment failure, further contributing to the prognostic predictivity of TP53 mutation.

Keywords:  CNV; Del 9p21.3 (CDKN2A); MCL; NGS; POD24; TP53; mantle cell lymphoma; prognosis

DOI:  https://doi.org/10.3390/cancers17244027
Cancers (Basel). 2025 Dec 13. pii: 3984. [Epub ahead of print]17(24):

Can TP53, TMB and TME Expand the Immunotherapy Benefit in Metastatic Colorectal Cancer?

Monia Specchia, Denise Drittone, Eva Mazzotti, Federica Mazzuca.

   BACKGROUND: Metastatic colorectal cancer (mCRC) with TP53 gene mutations, which are commonly found in tumors that are microsatellite stable (MSS) and not prone to genetic errors seen in some cancers, is associated with aggressive cancer behavior and poor outcomes. While MSI-high (MSI-H, referring to high levels of gene instability) disease benefits markedly from PD-1-based immunotherapy (drugs that inhibit the PD-1 protein on immune cells), TP53-mutated MSS tumors rarely receive immune checkpoint inhibitors (ICIs, drugs that help immune cells attack cancer) outside of trials and often only in later lines of therapy.
OBJECTIVE: We aimed to synthesize translational and clinical evidence regarding the effects of early rationale-driven immunotherapy combinations on survival outcomes, in TP53-mutated metastatic colorectal cancer, with a focus on practical clinical implications.
METHODS: This narrative review was conducted in accordance with SANRA criteria. Literature searches were performed in PubMed/MEDLINE, Scopus, and Web of Science (2010-2025). Relevant ESMO and NCCN guidelines and key references were also reviewed.
RESULTS: In KEYNOTE-177 study (MSI-H/dMMR), pembrolizumab improved PFS (HR 0.60) and showed durable OS with >5-year follow-up. CheckMate-142 reported sustained activity with nivolumab ± ipilimumab. Preclinical/early clinical data in MSS/TP53 suggest that ICIs may become effective when combined with priming (chemo/DDR) and vascular normalization (anti-VEGF), particularly in subsets with elevated TMB. The randomized ROME trial supports the clinical utility of genomically matched, NGS-guided strategies.
CONCLUSIONS: A precision approach integrating TP53 status, TMB, and TME modulation could extend the immunotherapy benefit beyond MSI-H to TP53-mutated MSS mCRC; prospective first-line trials are warranted.

Keywords:  TP53 mutation; immune checkpoint inhibitors; immunotherapy; metastatic colorectal cancer; microsatellite instability; precision oncology; tumor biomarkers

DOI:  https://doi.org/10.3390/cancers17243984