bims-p53act Biomed News
on p53 mutations and anti-cancer therapy response
Issue of 2026–02–15
six papers selected by
Toni Martínez Bernabé, Universitat de les Illes Balears
  1. Innovative Drug and Prodrug Candidates in Cancer Treatment Targeting TP53 Mutations: Challenge and Hope.
  2. Prognostic impact of TP53 mutations in diffuse large B-cell lymphoma.
  3. Artificial Intelligence-Enabled Integration Suggests TP53 Pathway Alterations as Prognostic Biomarkers in Populations with Disproportionate Health Burdens.
  4. Reduced LOXL3 Expression Disrupts Microtubule Acetylation and Drives TP53-Dependent Cell Fate in Glioblastoma.
  5. Radiotherapy in Li-Fraumeni Syndrome: From Biological Concern to Personalized Clinical Decision-Making.
  6. Ribosome biogenesis rate, a parameter of sensitivity to chemotherapeutic drugs inhibiting rRNA synthesis.
  1. Drug Dev Res. 2026 Apr;87(2): e70246
    Innovative Drug and Prodrug Candidates in Cancer Treatment Targeting TP53 Mutations: Challenge and Hope.
    Raed M Al-Zoubi, Mai Elaarag, Ayman A Zarour, Khalil Garada, Sally R Al-Zoubi, Zainab E Fares, Ahmad R Al-Qudimat, Mohanad Shkoor, Abbas Khan, Mona A Sawali, Hiba Bawadi, Zain Z Zakaria, Mazhar Al Zoubi, Abdelali Agouni, Khalid Alrumaihi.
      The TP53 gene encodes the tumor suppressor protein 53, which is critical for maintaining genomic stability and preventing tumorigenesis. Mutations in TP53, particularly missense mutations, have a substantial impact on cancer progression because they give gain-of-function features that enhance proliferation, metastasis, and treatment resistance. This review examines the mechanisms underlying p53 mutations, including their interactions with critical regulatory circuits, and assesses novel medication and prodrug options targeting TP53 mutations in various malignancies. Small-molecule correctors, statins, Hsp90 inhibitors, and new drugs like Eprenetapopt and COTI-2 are among the therapeutic options proposed. The mechanisms of action and potential efficacy in treating leukemia, lung, breast, and ovarian malignancies are investigated. Emerging techniques for restoring wild-type p53 functionality or degrading mutant p53 demonstrate the therapeutic potential of these approaches. Challenges such as medication resistance, side effects, and the chemical complexity of p53 pathways are also addressed, emphasizing the importance of ongoing research. This review contributes to our understanding of TP53-targeted cancer medicines, offering hope for more innovative treatments with improved outcomes.
    Keywords:  TP53 mutations; cancer therapy; gain‐of‐function mutations; mutant p53 degradation; p53 tumor suppressor; targeted therapies; wild‐type p53 reactivation
    DOI:  https://doi.org/10.1002/ddr.70246
  2. Ann Hematol. 2026 Feb 10. 105(3): 102
    Prognostic impact of TP53 mutations in diffuse large B-cell lymphoma.
    Jiayi Yu, Qiang He, Yuting Yan, Kuntong Liu, Rong Xie, Ji Ma, Liang Wang.
      
    Keywords:   TP53 mutation; Diffuse large b-cell lymphoma; Next-generation sequencing; Precision medicine; Prognosis
    DOI:  https://doi.org/10.1007/s00277-026-06882-9
  3. Int J Mol Sci. 2026 Feb 06. pii: 1607. [Epub ahead of print]27(3):
    Artificial Intelligence-Enabled Integration Suggests TP53 Pathway Alterations as Prognostic Biomarkers in Populations with Disproportionate Health Burdens.
    Fernando C Diaz, Brigette Waldrup, Francisco G Carranza, Sophia Manjarrez, Enrique Velazquez-Villarreal.
      The incidence of early-onset colorectal cancer (EOCRC; <50 years) continues to increase, with the most rapid rises occurring among Hispanic/Latino (H/L) populations who remain underrepresented in molecular research. Because the TP53 signaling pathway is a key driver of colorectal tumorigenesis, this study aimed to clarify its prognostic significance in FOLFOX-treated EOCRC across ancestry groups. We analyzed 2515 colorectal cancer (CRC) cases (266 H/L, 2249 non-Hispanic White [NHW]) stratified by ancestry, age at onset, and FOLFOX exposure. Fisher's exact, chi-square, and Kaplan-Meier's analyses were applied, and multi-dimensional data integration was performed using AI-HOPE and AI-HOPE-TP53, conversational artificial intelligence platforms enabling natural language-driven exploration of clinical, genomic, and therapeutic features. TP53 pathway alterations were common in both H/L (85%) and NHW (83%) FOLFOX-treated patients. Among late-onset NHW cases, FOLFOX treatment was associated with higher TP53 mutation frequencies and lower ATM and CDKN2A mutation rates compared with untreated counterparts, while CHEK2 alterations were significantly less frequent in late-onset H/L patients. Missense mutations were the predominant alteration type across groups. These findings suggest that TP53 pathway alterations may be associated with ancestry- and treatment-specific clinical patterns in EOCRC and illustrate how AI-enabled integrative analytic frameworks can facilitate hypothesis generation and prioritize candidate biomarkers for future validation in precision oncology.
    Keywords:  AI-agents; FOLFOX chemotherapy; Hispanic/Latino health disparities; TP53 signaling pathway; artificial intelligence; biomarkers; early-onset colorectal cancer; tumor suppressor
    DOI:  https://doi.org/10.3390/ijms27031607
  4. Cells. 2026 Jan 23. pii: 219. [Epub ahead of print]15(3):
    Reduced LOXL3 Expression Disrupts Microtubule Acetylation and Drives TP53-Dependent Cell Fate in Glioblastoma.
    Talita de Sousa Laurentino, Roseli da Silva Soares, Antônio Marcondes Lerario, Ricardo Cesar Cintra, Suely Kazue Nagahashi Marie, Sueli Mieko Oba-Shinjo.
      Glioblastoma (GBM) is the most aggressive primary brain tumor, marked by molecular heterogeneity and poor clinical prognosis. Lysyl oxidase-like 3 (LOXL3) is frequently upregulated in GBM, but its mechanistic contribution remains insufficiently defined. Here, we investigated the functional role of LOXL3 in GBM using CRISPR-Cas9-mediated LOXL3 knockdown in two genetically distinct GBM cell lines: U87MG (wild-type TP53) and U251 (mutant TP53). Reduced LOXL3 expression markedly reduced α-tubulin acetylation, particularly in U87MG cells, and downregulated genes involved in cell cycle progression and proliferation. Both cell lines exhibited mitotic defects, including delayed cell cycle progression and spindle abnormalities; however, cell fate diverged according to TP53 status. U87MG cells, sustained spindle checkpoint activation triggered a p53-dependent spindle checkpoint response culminating in apoptosis, while U251 cells underwent mitotic slippage and senescence. Transcriptomic analyses confirmed differential regulation of apoptosis versus senescence pathways in accordance with TP53 functionality. Additionally, reduced LOXL3 expression markedly impaired adhesion and migration in U87MG cells, whereas U251 cells were minimally affected, consistent with more pronounced microtubule destabilization. Collectively, these findings identify that LOXL3 is a key regulator of microtubule homeostasis, mitotic fidelity, adhesion, and invasive behavior in GBM. Targeting LOXL3 may therefore provide a therapeutic opportunity for genotype-informed intervention in GBM.
    Keywords:  LOXL3; TP53; adhesion; apoptosis; glioblastoma; senescence
    DOI:  https://doi.org/10.3390/cells15030219
  5. Cureus. 2026 Jan;18(1): e100978
    Radiotherapy in Li-Fraumeni Syndrome: From Biological Concern to Personalized Clinical Decision-Making.
    Reyzane El Mjabber, Rim Alami, Nada Filali, Abderrahim Bourial, Zineb Dahbi, Fadila Kouhen, Nabil Ismaili, Sanaa El Majjaoui, Asmaa Naim.
      Li-Fraumeni syndrome (LFS) is an inherited cancer predisposition syndrome caused by germline pathogenic variants in TP53. It is characterized by a high risk of developing malignancies throughout life, often at an early age. Because p53 is involved in cellular responses to DNA damage, the use of radiotherapy in this population has raised long-standing clinical concerns regarding potential late effects. This narrative review outlines key biological considerations related to radiation exposure in TP53 mutation carriers and summarizes the clinical experience reported with radiotherapy in patients with LFS. From a biological perspective, altered p53 function may influence how cells respond to ionizing radiation and how damaged cells are managed. These considerations have led to caution when considering radiotherapy in this setting. From a clinical perspective, the available literature remains limited and largely retrospective. Published reports describe variable outcomes after radiotherapy, including cases of secondary malignancies developing within previously irradiated regions, as well as cases without apparent long-term complications. Overall, clinical responses and long-term outcomes appear heterogeneous. In the absence of prospective data, radiotherapy in LFS should not be viewed as an absolute contraindication. Its use may be considered in selected clinical situations after careful multidisciplinary discussion. Decisions should balance the expected oncologic benefit with potential long-term risks and available alternatives. When radiotherapy is used, careful treatment planning to limit normal tissue exposure and long-term follow-up are essential components of patient care.
    Keywords:  li-fraumeni syndrome; radiation-induced malignancies; radiotherapy; secondary malignancies; tp53 germline mutation
    DOI:  https://doi.org/10.7759/cureus.100978
  6. Oncol Rev. 2025 ;19 1740261
    Ribosome biogenesis rate, a parameter of sensitivity to chemotherapeutic drugs inhibiting rRNA synthesis.
    Davide Treré, Lorenzo Montanaro, Massimo Derenzini, Claudio Agostinelli, Enrico Derenzini.
      Many drugs currently used in cancer chemotherapy exert their toxic action mainly by inhibiting ribosome biogenesis (RiBi). This is due to the fact that after inhibition of rRNA transcription ribosomal proteins, no longer used for ribosome building, bind to and neutralize the activity of the murine double minute 2 protein (MDM2, HMD2 in humans), thus hindering cell proliferation and possibly inducing apoptotic cell death. Here, we discuss the existing literature showing how RiBi rate and genomic alterations of ribosomal proteins (RP mutations/deletions) influence the degree of MDM2 inhibition after treatment with RiBi inhibitors in cancer cells. There is evidence that a high RiBi rate is associated with a high RPs release with strong inhibition of MDM2 activity and consequent induction of apoptotic cell death in response to RiBi inhibitors, whereas a low RiBi rate or RP mutations/deletions are associated with a degree of MDM2 inhibition insufficient to kill cancer cells. In the latter case, in cells with wild type p53, association with drugs which stabilize p53 with different mechanisms may overcome cancer cells resistance to RiBi inhibition, whereas in cancers lacking functional p53 addition of MDM2 inhibitors should be considered. From this, the necessity to evaluate the rate of ribosome biogenesis together with the presence of RP mutations/deletions in cancer tissues for predicting the sensitivity of cancer cells to RiBi inhibitors in order to choose more appropriate therapeutic protocols.
    Keywords:  MDM2; cancer; chemotherapy; p53; rRNA synthesis; ribosomal proteins; ribosome biogenesis
    DOI:  https://doi.org/10.3389/or.2025.1740261
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