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p53: from understanding its structure to advances in therapeutic targeting
Open accessAbstract
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.
Overview
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TL;DR
This review synthesizes p53 structure, inactivation, biological roles, and therapeutic strategies across cancer and nonneoplastic diseases. It highlights that TP53 is the most commonly mutated cancer gene, that p53 remains largely “undruggable” clinically, and that MDM2/4 antagonists, mutant-p53 reactivators, immunotherapy, and gene therapy are advancing but mostly in early trials.
Key findings
- TP53 mutations occur in more than 50% of all human malignancies and exceed 70% in squamous esophageal cancer, small-cell lung cancer, squamous cell lung cancer, and complex karyotype AML; rates are lower in lymphoma, melanoma, and overall AML. Most TP53 mutations are missense, with hotspots including G245, R249, R248, R282, R273, Y220, and R175, and exons 5, 7, and 8 are common mutation sites.
- p53 is a 393-amino-acid protein with five domains (TAD 1–61, PRD 62–94, DBD 95–292, TD 325–356, CTD 357–393) and regulates apoptosis, cell cycle arrest, senescence, autophagy, ferroptosis, metabolism, DNA repair, and the tumor immune microenvironment. Mutant p53 can exert dominant-negative and gain-of-function effects and aggregate, contributing to tumor progression and therapy resistance.
- Therapeutic small molecules include broad-spectrum mutant-p53 reactivators (e.g., CP31398, PRIMA-1/APR-246, ATO, ReACp53, ADH-6, L1/LH), allele-specific compounds (e.g., PC14586 for Y220C, ZMC1 for R175H, COTI-2), and MDM2/4 inhibitors. Clinical examples: APR-246 plus azacitidine in TP53-mutant MDS/AML gave 1-year RFS 58% and median OS 19.3 months after transplant; APR-246 plus venetoclax with or without azacitidine in TP53-mutated AML had ORR 64% (25/39), CRR 38% (15/39), no DLTs, and ≥grade 3 febrile neutropenia in 47% (23/49).
- In phase I/II NCT04585750, PC14586 in advanced solid tumors with TP53 Y220C mutation produced 5 partial responses and 7 stable disease among 21 evaluable patients, with mostly grade 1/2 adverse effects. Immunotherapy (vaccines, TCR-like/bispecific antibodies) and gene therapy (adenovirus, nanoparticles, siRNA, CRISPR–Cas9/base editing) show potential but remain early or face safety/delivery challenges.
Methods
- Design: narrative review, not a primary research study; it synthesizes p53 structure, inactivation, disease roles, and therapeutic targeting in cancer and nonneoplastic diseases.
- Data/sample: cited literature, figures/tables of p53 domain structure, mutation data from the TP53 database (http://p53.fr/tp53-database/mutation-database), compound tables, and clinical trial tables with NCT identifiers (Tables 3 and 4).
- Analysis: descriptive and comparative synthesis of mechanistic studies, preclinical models, and clinical trials; no systematic search, inclusion/exclusion criteria, meta-analysis, or quantitative pooling is reported.
Limitations
- Stated: drugs targeting p53 are still in early clinical trials and none have been approved by the FDA or EMA; most clinical trials are phase I/II, some did not meet primary endpoints and reported DLTs. Mutant p53 heterogeneity means one compound may be effective against only one or a few mutants, and the specific mechanisms of many compounds are unclear. Pure MDM4 inhibitors and MDM2/4 bispecific inhibitors are lacking, and MDM2/4 inhibitors may cause toxicity in normal cells by stabilizing wild-type p53.
- Stated: gene therapy faces challenges in technology maturity, safety, efficacy, delivery, immunogenicity, liver clearance, and patient acceptance; immunotherapy toxicity is difficult to predict/control because understanding of immunotherapy processes is incomplete. Therapeutics for nonneoplastic diseases are less explored, and p53 inhibition risks tumorigenesis.
- Evident from text: as a narrative review, it does not report a systematic literature search, quality/risk-of-bias assessment, or quantitative synthesis; clinical trial coverage is described as partial in tables. The paper also repeatedly notes unresolved or conflicting findings, such as differing mechanisms of CP31398 and APR-246 and context-dependent roles of p53 in metabolic diseases.
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In the paper
“Exons 5, 7, and 8 are the most common sites for mutations in TP53 (Fig. 5c).”
§ p53: from understanding its structure to advances in therapeutic targeting > Structure, inactivation, and roles of p53 in diseases > Inactivation of p53
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In the paper
“Although TP53 mutations are widespread in many tumor types, the TP53 mutation rates differ across different organs (Fig. 5b).”
§ p53: from understanding its structure to advances in therapeutic targeting > Structure, inactivation, and roles of p53 in diseases > Inactivation of p53
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None of the sources cited for this claim have been checked yet.
In the paper
“Notably, CRISPR–Cas9 can induce DNA damage-triggered p53 activation in cells expressing wild-type p53, promoting cell cycle arrest or cell death.408,410,411”
§ p53: from understanding its structure to advances in therapeutic targeting > Therapeutic strategies targeting p53 in cancer > Gene therapies
What the sources say
- Not checked yetcites [408] Funk, J. S. et al. Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations. Nat. Genet. 57, 140–153 (2025). source
- Not checked yetcites [410] Enache, O. M. et al. Cas9 activates the p53 pathway and selects for p53-inactivating mutations. Nat. Genet. 52, 662–668 (2020). source
- Not checked yetcites [411] Ihry, R. J. et al. p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells. Nat. Med. 24, 939–946 (2018). source
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“However, approximately 15%-20% of patients who discontinue the use of dopamine agonists experience withdrawal symptoms such as panic attacks, anxiety, diaphoresis, irritability, and pain.440”
§ p53: from understanding its structure to advances in therapeutic targeting > Therapeutics for nonneoplastic diseases > Neurodegenerative diseases
What the sources say
- Not checked yetcites [440] Pondal, M. et al. Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic. J. Neurol. Neurosurg. Psychiatry 84, 130–135 (2013). source
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In the paper
“Compared with patients treated with levodopa, more patients treated with MAO-B inhibitors and dopamine agonists terminate treatment because of adverse events.438”
§ p53: from understanding its structure to advances in therapeutic targeting > Therapeutics for nonneoplastic diseases > Neurodegenerative diseases
What the sources say
- Not checked yetcites [438] Gray, R. et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson’s disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet 384, 1196–1205 (2014). source
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Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ p53: from understanding its structure to advances in therapeutic targeting > Introduction
“none of these compounds have been approved for use by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA).”
§ p53: from understanding its structure to advances in therapeutic targeting > Therapeutic strategies targeting p53 in cancer > Small-molecule drugs
“The FDA subsequently granted the APR-246 orphan drug name and approved APR-246 for MDS treatment.”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ p53: from understanding its structure to advances in therapeutic targeting > Introduction
“none of these compounds have been approved for use by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA).”
§ p53: from understanding its structure to advances in therapeutic targeting > Therapeutic strategies targeting p53 in cancer > Small-molecule drugs
“AMG-232 was approved by the FDA following this trial.”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ p53: from understanding its structure to advances in therapeutic targeting > Structure, inactivation, and roles of p53 in diseases > p53 structural domains and their functional implications
“PAI-1), a p53 target gene, is a marker of senescence and is necessary for replicative senescence.”
§ p53: from understanding its structure to advances in therapeutic targeting > Structure, inactivation, and roles of p53 in diseases > p53 structural domains and their functional implications
“The suppression of PAI-1 induces replicative senescence.”
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In the paper
§ p53: from understanding its structure to advances in therapeutic targeting > Therapeutic strategies targeting p53 in cancer > Small-molecule drugs
“Table 3 Partial FDA-approved drugs and clinical trials for the treatment of nonneoplastic diseases, including NDDs and metabolic diseases”
§ p53: from understanding its structure to advances in therapeutic targeting > Therapeutic strategies targeting p53 in cancer > Small-molecule drugs
“| APR-246 | NCT00900614 | I | Multiple cancers | 36 | Completed | 2009/05–2010/10 | https://clinicaltrials.gov/search?term=NCT00900614 |”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ p53: from understanding its structure to advances in therapeutic targeting > Abstract
“drugs targeting p53 are still under investigation in early clinical trials and have not been approved for clinical use.”
§ p53: from understanding its structure to advances in therapeutic targeting > Therapeutic strategies targeting p53 in cancer > Gene therapies
“Gendicine, the first p53 gene therapy, is a recombinant human p53 adenovirus that was approved in 2003 by the China Food and Drug Administration (CFDA) for the treatment of HNSCC.”
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Citations
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Cited by
Fang, Y., Wu, Z., Guo, R., Wang, C., Qin, Y., Dong, Y., Li, A., Liu, A., Jia, C., Han, T., et al. (2026) · Advanced Science · doi:10.1002/advs.77237 · Cited by 2
Wang, H., Zhang, Y., Liu, D., Liu, C., Wu, S., Wu, Z., Cui, T., Yu, G., Xu, Y., Yang, W., et al. (2026) · Cancer Letters · doi:10.1016/j.canlet.2026.218831 · Cited by 2
G-quadruplex targeting by CX-5461 as a novel therapeutic strategy in testicular germ cell tumorsPreprint
Islam, R., Liesen, A., Rodríguez-Roque, C. S., Paeschke, K., & Schorle, H. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.04.749562 · Cited by 1
Autophagy, apoptosis, and cellular homeostasis: A physiological perspective
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Metadata
- Authors
- Wang, W., Liu, X., Liu, H., Abolhassani, H., Yan, H., Zhang, H., & Wang, X.
- Affiliations
- Tianjin Medical University Cancer Institute and Hospital (CN)
- Children's Medical Center (IR)
- Corresponding author
- Zhang, Huilai
- Wang, Xianhuo
- Venue
- Signal Transduction and Targeted Therapy
- Published
- 2026-04-06
- Volume
- 11
- Issue
- 1
- ISSN
- 2059-3635 (ISSN-L)
- PMC
- PMC13053732
- OpenAlex
- W7150759957
- Semantic Scholar
- 384f5f10a34b983a2fe657f5f2886e1f3669ed92
- Cited by
- 30
- References
- 496
- Citations by year
- 2026: 29
- FWCI
- 21.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- creativecommons.org/licenses/by-nc-nd/4.0 (tdm)
- creativecommons.org/licenses/by-nc-nd/4.0 (vor)
- Locations
- Signal Transduction and Targeted Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (W2412122, 82200208, 8247012736)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Keywords
- p53, TP53, tumor suppressor, p53 inactivation, TP53 mutation, p53-targeted therapy, p53 restoration, undruggable targets, apoptosis, autophagy, cell cycle arrest, senescence, tumor immune microenvironment
- MeSH terms
- Animals, Humans, Neoplasms, Tumor Suppressor Protein p53, Drug Discovery, Molecular Targeted Therapy
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- Wang, W., Liu, X., Liu, H., Abolhassani, H., Yan, H., Zhang, H., & Wang, X. (2026). p53: from understanding its structure to advances in therapeutic targeting. Signal Transduction and Targeted Therapy. https://doi.org/10.1038/s41392-025-02549-5
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