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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Background
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BackgroundInfluential
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Background
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Background
Mutant p53 achieved Gain-of-Function by promoting tumor growth and immune escape through PHLPP2/AKT/PD-L1 pathway
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EIF5A1 promotes epithelial ovarian cancer proliferation and progression
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An integrated view of p53 dynamics, function, and reactivation
Demir, Ö., de Barros, E. P., Offutt, T. L., Rosenfeld, M. A., & Amaro, R. E. (2021) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2020.11.005 · Cited by 28
“Because of mutant p53’s frequent involvement in cancer progression, it is thought of as a promising and exciting drug target in the field of cancer therapy [1,2].”
Background
Clinical significance of TP53 mutations in adult T‐cell leukemia/lymphoma
Sakamoto, Y., Ishida, T., Masaki, A., Murase, T., Takeshita, M., Muto, R., Iwasaki, H., Ito, A., Kusumoto, S., Nakano, N., et al. (2021) · British Journal of Haematology · doi:10.1111/bjh.17749 · Cited by 28
The Genetic Evolution of Metastasis
Rogiers, A., Lobón, I., Spain, L. A., & Turajlic, S. (2022) · Cancer Research · doi:10.1158/0008-5472.can-21-3863 · Cited by 29
Current insights into the regulation of programmed cell death by TP53 mutation in cancer
Su, Y., Sai, Y., Zhou, L., Liu, Z., Du, P., Wu, J., & Zhang, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1023427 · Cited by 29
Potential role of p53 deregulation in modulating immune responses in human malignancies: A paradigm to develop immunotherapy
Chauhan, S., Jaiswal, S., Jakhmola, V., Singh, B. P., Bhattacharya, S., Garg, M., & Sengupta, S. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216766 · Cited by 29
HMGA2 promotes intestinal tumorigenesis by facilitating MDM2‐mediated ubiquitination and degradation of p53
Wang, Y., Hu, L. T., Wang, J., Li, X., Sahengbieke, S., Wu, J., & Lai, M. (2018) · The Journal of Pathology · doi:10.1002/path.5164 · Cited by 29
“However, the p53 mutant phenotype leads to abnormal p53 stabilization and mutant p53 protein overexpression [24,25].”
Background
Rescue of p53 functions by in vitro‐transcribed mRNA impedes the growth of high‐grade serous ovarian cancer
Raab, M., Kostova, I., Peña‐Llopis, S., Fietz, D., Kressin, M., Aberoumandi, S. M., Ullrich, E., Becker, S., Sanhaji, M., & Strebhardt, K. (2023) · 癌症：英文版 · doi:10.1002/cac2.12511 · Cited by 27
Ferroptosis-associated genes and compounds in renal cell carcinoma
He, C., Li, Q., Wu, W., Liu, K., Li, X., Zheng, H., & Lai, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1473203 · Cited by 29
“Approximately 50% of patients with cancer have a p53 gene mutation that leads to the inactivation of wild-type p53 (64).”
Background
Multifaceted role of TRIM28 in health and disease
Maghsoudloo, M., Mokhtari, K., Jamali, B., Gholamzad, A., Entezari, M., Hashemi, M., & Fu, J. (2024) · MedComm · doi:10.1002/mco2.790 · Cited by 29
Salvation of the fallen angel: Reactivating mutant p53
Yang, L., Wang, Z., Chen, Y., Petersen, R. B., Zheng, L., & Huang, K. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14572 · Cited by 27
“Almost all low MW mutp53 reactivators have broad side effects (Bykov et al., 2018).”
Background
Oridonin induces Mdm2‐p60 to promote p53‐mediated apoptosis and cell cycle arrest in neuroblastoma
Zhu, H., Zhang, C., Zhu-ying, G., Yang, J., Guo, J., Chen, C., Yao, Q., Liu, F., Zhang, Q., & Gao, F. (2019) · Cancer Medicine · doi:10.1002/cam4.2393 · Cited by 27
Drug-induced modifications and modulations of microRNAs and long non-coding RNAs for future therapy against Glioblastoma Multiforme
Ramaiah, M. J., Karthikeyan, D., Kumar, S. K., & Yamajala, R. B. R. D. (2019) · Gene · doi:10.1016/j.gene.2019.144126 · Cited by 27
Regulation of p53 by E3s
Pan, M., & Blattner, C. (2021) · Cancers · doi:10.3390/cancers13040745 · Cited by 27
P53-independent partial restoration of the p53 pathway in tumors with mutated p53 through ATF4 transcriptional modulation by ERK1/2 and CDK9
Tian, X., Ahsan, N., Lulla, A. R., Lev, A., Abbosh, P. H., Dicker, D. T., Zhang, S., & El‐Deiry, W. S. (2021) · Neoplasia · doi:10.1016/j.neo.2021.01.004 · Cited by 27
Arginine Methyltransferase PRMT1 Regulates p53 Activity in Breast Cancer
Liu, L.-M., Tang, Q., Hu, X., Zhao, J., Zhang, Y., Ying, G., & Zhang, F. (2021) · Life · doi:10.3390/life11080789 · Cited by 28
“It has been considered as one of the most frequently mutated genes in human cancers [1].”
Background
TP53 and CDKN2A mutations in patients with early-stage lung squamous cell carcinoma: an analysis of the correlations and prognostic outcomes
Wang, P., Wang, F., He, H., Chen, Y., Lin, H. M., Chen, P., Chen, X., & Liu, S. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-3709 · Cited by 27
“TP53 encodes the tumor suppressor protein p53, binds directly to chromatin in the nucleus, and plays an important role in the regulation of the cell cycle, apoptosis, autophagy, and DNA repair in response to oncogenic stress (3).”
BackgroundResult
Assessment of Thermal Stability of Mutant p53 Proteins via Differential Scanning Fluorimetry
Khadiullina, R., Mirgayazova, R., Davletshin, D., Khusainova, E., Chasov, V. V., & Bulatov, E. (2022) · Life · doi:10.3390/life13010031 · Cited by 27
Multifunctional Compounds for Activation of the p53‐Y220C Mutant in Cancer
Miller, J. J., Orvain, C., Jozi, S., Clarke, R. M., Smith, J. R., Blanchet, A., Gaiddon, C., Warren, J. J., & Storr, T. (2018) · Chemistry - A European Journal · doi:10.1002/chem.201802677 · Cited by 26
Relevance function of microRNA-708 in the pathogenesis of cancer
Sun, S., Hu, S., Shang, Y.-P., Li, L., Zhou, H., Chen, J.-S., Yang, J., Li, J., Huang, Q., Shen, C., et al. (2019) · Cellular Signalling · doi:10.1016/j.cellsig.2019.109390 · Cited by 27
Decrypting the Molecular Mechanistic Pathways Delineating the Chemotherapeutic Potential of Ruthenium-Phloretin Complex in Colon Carcinoma Correlated with the Oxidative Status and Increased Apoptotic Events
Jin, G., Zhao, Z., Chakraborty, T., Mandal, A., Roy, A., Roy, S., & Guo, Z. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/7690845 · Cited by 26
“Mutation of TP53 and the simultaneous inactivation of p53 suppress tumor cell death and progression [68].”
Background
p53 and ANXA4/NF‑κB p50 complexes regulate cell proliferation, apoptosis and tumor progression in ovarian clear cell carcinoma
Liu, J., Wang, H., Zheng, M., Deng, L., Zhang, X., & Lin, B. (2020) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2020.4757 · Cited by 26
“Wild-type p53, a key factor in regulating cell-cycle arrest, cell aging and apoptosis, is the most effective tumor-inhibiting gene, whereby exogenously-acquired wild-type p53 can inhibit autophagy, reverse drug resistance and promote apoptosis of tumor cells (19).”
Background
The role of tripartite motif-containing 28 in cancer progression and its therapeutic potentials
Yang, Y., Tan, S., Han, Y.-Q., Huang, L., Yang, R., Hu, Z., Tao, Y., Oyang, L., Lin, J.-G., Peng, Q., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1100134 · Cited by 18
“One of the best-known tumor suppressor, TP53, encodes the p53 protein, which is frequently deleted or inactivated by mutations in cancer (19, 20).”
Background
p53 biology and reactivation for improved therapy in MDS and AML
Zawacka‐Pankau, J. (2024) · Biomarker Research · doi:10.1186/s40364-024-00579-9 · Cited by 25
Profiles of Immune Infiltration in Bladder Cancer and its Clinical Significance: an Integrative Genomic Analysis
Wu, Z., Zhu, K., Liu, Q., Liu, Y., Chen, L., Cui, J., Guo, H., Zhou, N., Zhu, Y., Li, Y., et al. (2020) · International Journal of Medical Sciences · doi:10.7150/ijms.42151 · Cited by 25
“The tumor suppressor gene TP53 has been reported to be mutated in more than 50% of human malignancies, and thus, promote the development and progression of cancer [29].”
Background
Exosomes as Biomarkers of Human and Feline Mammary Tumours; A Comparative Medicine Approach to Unravelling the Aggressiveness of TNBC
Howard, J., Wyse, C. A., Argyle, D. J., Quinn, C., Kelly, P., & McCann, A. H. (2020) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2020.188431 · Cited by 25
“mutant p53 in TNBC, and also supported previous reports, demonstrating that, in addition to inhibiting the growth of mutant p53 cell lines, COTI-2 also inhibited the proliferation of p53 wildtype cells [18,32].”
Result
Targeting p53 in chronic lymphocytic leukemia
Moia, R., Boggione, P., Mahmoud, A. M., Kodipad, A. A., Adhinaveni, R., Sagiraju, S., Patriarca, A., & Gaïdano, G. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1832465 · Cited by 25
Expression and prognostic significance of m6A‐related genes in TP53‐mutant non‐small‐cell lung cancer
Zhao, Z., Wan, J., Guo, M., Wang, Y., Yang, Z., Zhou, F., Li, Z., & Ming, L. (2021) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.24118 · Cited by 24
Krüppel-Like Factor 4 and Its Activator APTO-253 Induce NOXA-Mediated, p53-Independent Apoptosis in Triple-Negative Breast Cancer Cells
Nakajima, W., Miyazaki, K., Asano, Y., Kubota, S., & Tanaka, N. (2021) · Genes · doi:10.3390/genes12040539 · Cited by 25
“For example, these include mutant p53 re-activating agents and inhibitors of p53 E3 ubiquitin ligase MDM2 [21,22].”
Background
Induction of Apoptosis and Autophagy by Ternary Copper Complex Towards Breast Cancer Cells
Lee, Z. Y., Leong, C. H., Lim, K. U. L., Wong, C. C. S., Pongtheerawan, P., Arikrishnan, S., Tan, K. L., Loh, J. S., Low, M. L., How, C. W., et al. (2021) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520621666210726132543 · Cited by 27
Green tea-derived theabrownin induces cellular senescence and apoptosis of hepatocellular carcinoma through p53 signaling activation and bypassed JNK signaling suppression
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Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma
Li, L., Wang, X., Xu, H., Liu, X., & Xu, K. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.947208 · Cited by 25
“Studies have shown that deletion or mutation of the p53 gene leads to loss of wild-type p53 activity and malignant transformation of tumors (Bykov et al., 2018; Levine, 2020).”
Background
Bioinformatics analysis of BIRC5 in human cancers
Ye, H.-B., Baojun, M., Meng, G.-Q., Tao, S., Wang, Y., Chen, Z., Zhao, W., Ren, B.-Y., & Ye, Z. (2022) · Annals of Translational Medicine · doi:10.21037/atm-22-3496 · Cited by 25
“P53, also known as TP53, has been proven to be a tumor suppressor gene associated with tumorigenesis (25,26).”
GOF Mutant p53 in Cancers: A Therapeutic Challenge
Dolma, L., & Muller, P. A. J. (2022) · Cancers · doi:10.3390/cancers14205091 · Cited by 29
“This was attributed to the synergistic crosstalk between APR-246′s reactivation of mutp53 sensitizing the tumour cells to the DNA damaging agents [65].”
BackgroundInfluential
Engineered a dual-targeting HA-TPP/A nanoparticle for combination therapy against KRAS-TP53 co-mutation in gastrointestinal cancers
Mei, Y., Qin, X., Yang, Z., Song, S., Liu, X., Wu, C., Qian, J., Huang, X., Zhang, Y., & He, W. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.10.003 · Cited by 27
“Of these strategies, the elimination of mutp53 is probably the most straightforward strategy [28 – 30], and various agents being re-ported gradually in recent years, including small molecules and nano-materials [31 – 34].”
Pharmacological targets and molecular mechanisms of plumbagin to treat colorectal cancer: A systematic pharmacology study
Liang, Y., Zhou, R., Liang, X., Kong, X., & Yang, B. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.173227 · Cited by 25
Cross‐talk between Myc and p53 in B‐cell lymphomas
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“Other studies support many novel agents that may have potential as therapy for B-cell lymphomas with TP53 mutation.(93) Targeting the p53/p21 axis might be an alternative treatment strategy.”
Background
Histone H2A-peptide-hybrided upconversion mesoporous silica nanoparticles for bortezomib/p53 delivery and apoptosis induction
Rong, J., Li, P., Ge, Y., Chen, H., Wu, J., Zhang, R., Lao, J., Lou, D., & Zhang, Y. (2019) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2019.110674 · Cited by 24
L-Glucose: Another Path to Cancer Cells
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A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer
Grzes, M., Oroń, M., Staszczak, Z., Jaiswar, A., Nowak-Niezgoda, M., & Walerych, D. (2020) · Cancers · doi:10.3390/cancers12061532 · Cited by 24
“The only dedicated agent in clinical trials against mutant p53 is APR-246 (PRIMA-1MET) which restores features of WT p53 activity, but also inhibits mutant p53 GOF [52].”
BackgroundInfluential
GenOrigin: A comprehensive protein-coding gene origination database on the evolutionary timescale of life
Tong, Y., Shi, M., Qian, S. H., Chen, Y., Luo, Z.-H., Tu, Y., Xiong, Y.-L., Geng, Y.-J., Chen, C., & Chen, Z. (2021) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2021.03.018 · Cited by 24
Redox Sensitive Cysteine Residues as Crucial Regulators of Wild-Type and Mutant p53 Isoforms
Butturini, E., Butera, G., Pacchiana, R., de Prati, A. C., Mariotto, S., & Donadelli, M. (2021) · Cells · doi:10.3390/cells10113149 · Cited by 25
PPM1D Is a Therapeutic Target in Childhood Neural Tumors
Milosevic, J., Treis, D., Fransson, S. M., Gallo-Oller, G., Sveinbjørnsson, B., Eißler, N., Tanino, K., Sakaguchi, K., Martinsson, T., Wickström, M., et al. (2021) · Cancers · doi:10.3390/cancers13236042 · Cited by 23
“Dysregulation of p53 results in genomic instability, uncontrolled cell division and inhibition of apoptosis [3,4].”
Background

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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