Cited by 893Cancer-related Molecular PathwaysPI3K/AKT/mTOR signaling in cancerCell death mechanisms and regulation

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Targeting mutant p53 for efficient cancer therapy

Bykov, Vladimir J. N., Eriksson, Sofi E., Bianchi, Julie, Wiman, Klas G.·2018·Nature Reviews Cancer

DOI 10.1038/nrc.2017.109

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Abstract

The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. Wild-type p53 can suppress tumour development by multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour cell death and rapid tumour progression. The high frequency of TP53 mutation in tumours has prompted efforts to restore normal function of mutant p53 and thereby trigger tumour cell death and tumour elimination. Small molecules that can reactivate missense-mutant p53 protein have been identified by different strategies, and two compounds are being tested in clinical trials. Novel approaches for targeting TP53 nonsense mutations are also underway. This Review discusses recent progress in pharmacological reactivation of mutant p53 and highlights problems and promises with these strategies.

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BackgroundInfluential
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Background
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“Given the importance of p53 in homeostatic regulation of immune responses, malfunction of p53, due to its deficient expression and mutation, exerts detrimental effect in the pathogenesis of cancer and autoimmune diseases [11, 12].”
Background
Antigenic Targets for the Immunotherapy of Acute Myeloid Leukaemia
Khan, G. N., Orchard, K. H., & Guinn, B. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8020134 · Cited by 8
“By targeting p53, you prevent its support of further tumour growth and genomic instability [23].”
Background
Nucleotide variations of TP53 exon 4 found in intracranial meningioma and in�silico prediction of their significance
Bukovac, A., Kafka, A., Hrašćan, R., Vladušić, T., & Pećina‐Šlaus, N. (2019) · Molecular and Clinical Oncology · doi:10.3892/mco.2019.1936 · Cited by 8
“It is also important to take into account that a fraction of TP53 mutations represent frameshift mutations that ultimately lead to nonsense that will produce truncated p53 proteins with impaired wild‐type function (18).”
BackgroundInfluential
Ultrasound image analysis technology under deep belief networks in evaluation on the effects of diagnosis and chemotherapy of cervical cancer
Zhou, H.-Z., Wang, S., Zhang, T., Liu, D., & Yang, K. (2020) · The Journal of Supercomputing · doi:10.1007/s11227-020-03421-9 · Cited by 8
Clinical Outcomes of Children With Adrenocortical Carcinoma in the Context of Germline TP53 Status
Brenna, C. T. A., Michaeli, O., Wasserman, J. D., & Malkin, D. M. (2020) · Journal of Pediatric Hematology/Oncology · doi:10.1097/mph.0000000000001982 · Cited by 8
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The P53–P21–RB1 pathway promotes BRD4 degradation in liver cancer through USP1
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“However, TP53 is also the most frequently dysregulated tumor suppressor gene across many cancer types including liver cancer (17).”
Exploring the Spectrum of Long Non-Coding RNA CARMN in Physiological and Pathological Contexts
Li, H., Sun, C., Luo, B., Zhan, C., Li, W., Deng, L., Kang, K., & Gou, D. (2024) · Biomolecules · doi:10.3390/biom14080954 · Cited by 7
Integrated stress response (ISR) activation and apoptosis through HRI kinase by PG3 and other p53 pathway-restoring cancer therapeutics
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Machine learning-based ultrasound radiomics for predicting TP53 mutation status in hepatocellular carcinoma
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“Furthermore, TP53 has emerged as a promising target for antitumor therapies, demonstrating significant clinical potential in HCC-targeted treatments (23).”
T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development
Thomas, X. (2022) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2023.2161361 · Cited by 7
“Novel agents that reactivate mutant P53 are currently under clinical investigation [43].”
Background
Molecular dynamics simulations suggest Thiosemicarbazones can bind p53 cancer mutant R175H
Das, T., & Mukhopadhyay, C. (2023) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2023.140903 · Cited by 7
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p53 Genetics and Biology in Lung Carcinomas: Insights, Implications and Clinical Applications
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“Efforts to destabilize mutant p53 and thwart its GOF activities are actively explored as a hopeful therapeutic strategy for cancers with p53 mutations [23,48,66–68].”
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Kalmouni, M., Oh, Y., Alata, W., & Magzoub, M. M. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16111443 · Cited by 7
“Consequently, p53 plays a crucial role in cancer research and is a key target for developing cancer treatments [210,211].”
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“In over 50% of tumor cells, p53 is inactivated by mutations [27, 49, 50], and mutant p53 aggregates within cells to promote cancer progression, invasion, and metastasis [51, 52].”
Targeting Triple Negative Breast Cancer with a Nucleus-Directed p53 Tetramerization Domain Peptide
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Association between Predicted Effects of TP53 Missense Variants on Protein Conformation and Their Phenotypic Presentation as Li-Fraumeni Syndrome or Hereditary Breast Cancer
Liu, Y., Axell, O., van Leeuwen, T., Konrat, R., Kharaziha, P., Larsson, C., Wright, A. P. H., & Bajalica‐Lagercrantz, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126345 · Cited by 7
“, CP-31398 and APR-246) have been shown to restore wild-type functionality to mutant TP53 proteins by increasing their thermal stability [21].”
Background
The Current Understanding of and Treatment Paradigm for Newly-Diagnosed TP53-Mutated Acute Myeloid Leukemia
Shallis, R. M., Stahl, M. F., Bewersdorf, J. P., & Zeidan, A. M. (2021) · Hemato · doi:10.3390/hemato2040051 · Cited by 7
“1, encodes the transcription factor and tumor suppressor p53 whose cellular levels increase in response to deoxyribonucleic acid (DNA) damage among other cellular stressors; the consequent transcription of numerous p53 target genes, including those responsible for DNA damage repair, cell cycling and differentiation, i…”
Background
Wild-type p53 suppresses formin-binding protein-17 (FBP17) to reduce invasion
Suman, P., Mehta, V., Craig, A. W., & Chander, H. (2022) · Carcinogenesis · doi:10.1093/carcin/bgac015 · Cited by 7
Non-Small-Cell Lung Cancer Patients Harboring TP53/KRAS Co-Mutation could Benefit from a PD-L1 Inhibitor
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Anti-inflammatory effects of PRIMA-1MET (mutant p53 reactivator) induced by inhibition of nuclear factor-κB on rheumatoid arthritis fibroblast-like synoviocytes
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“Since PRIMA1MET affects multiple targets and pathways, it is possible that downregulation of p53 is not a direct effect of PRIMA-1MET and is related to the activation of other regulatory proteins (Bykov et al. 2018; Rangel et al. 2019).”
Background
Target recognition assisted-primer exchange reaction (Ta-PER) for sensitive analysis of p53 gene and its application in analyzing amatoxin-treated samples
Zhao, K., Fu, W., Huang, Z., Chen, R., Lin, W., & Lin, Z. (2022) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-022-04420-w · Cited by 7
Mutation patterns and evolutionary action score of TP53 enable identification of a patient population with poor prognosis in advanced non‐small cell lung cancer
Jiang, W., Cheng, H., Yu, L., Zhang, J., Wang, Y., Liang, Y., Lou, F., Wang, H., & Cao, S. (2022) · Cancer Medicine · doi:10.1002/cam4.5447 · Cited by 8
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“However, mutations in TP53 and the resulting p53 inactivation allow evasion of tumor cell death and rapid tumor progression (Bykov et al. 2018).”
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Lyakhova, I., Piatkova, M. A., Gulaia, V. S., Romanishin, A. O., Shmelev, M. E., Bryukhovetskiy, A. S., Sharma, A., Sharma, H. S., Khotimchenko, R., & Bryukhovetskiy, I. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.03.010 · Cited by 7
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ZBTB7A interferes with the RPL5‐P53 feedback loop and reduces endoplasmic reticulum stress‐induced apoptosis of pancreatic cancer cells
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A New Ferroptosis-Related Long Non-Coding RNA Risk Model Predicts the Prognosis of Patients With Papillary Thyroid Cancer
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Colletofragarone A2 Inhibits Cancer Cell Growth In Vivo and Leads to the Degradation and Aggregation of Mutant p53
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Authors: Bykov, V. J. N., Eriksson, S. E., Bianchi, J., & Wiman, K. G.
Affiliations: Karolinska Institutet (SE)
Corresponding author: Wiman, Klas G.
ORCID: Bykov, Vladimir J. N.
Eriksson, Sofi E.
Bianchi, Julie
Wiman, Klas G.
Venue: Nature Reviews Cancer
Publisher: Springer Science and Business Media LLC
Published: 2017-12-15
Volume: 18
Issue: 2
Pages: 89-102
ISSN: 1474-175X (ISSN-L)
1474-1768
DOI: 10.1038/nrc.2017.109
OpenAlex: W2772062014
Cited by: 889
References: 159
Citations by year: 2026: 43 · 2025: 70 · 2024: 100 · 2023: 132 · 2022: 126 · 2021: 150 · 2020: 129 · 2019: 88 · 2018: 49 · 2017: 1
FWCI: 7.67
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Cancer (publishedVersion)
PubMed (publishedVersion)
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 › Molecular Biology › Cell death mechanisms and regulation
Keywords: TP53, mutant p53, p53 reactivation, missense mutations, nonsense mutation, tumor suppressor, cancer therapy, cancer cell death, clinical trials
MeSH terms: Animals, Antineoplastic Agents, Humans, Mutation, Neoplasms, Tumor Suppressor Protein p53, Cell Death, Mutant Proteins

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Targeting mutant p53 for efficient cancer therapy

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