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Targeting mutant p53 for efficient cancer therapy
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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“In addition to the abovementioned GOF, p53 mutants are also found to induce angiogenesis, enable replicative immortality, regulate GTPase activity and so on, which have been elaborately discussed in other review articles (Freed-Pastor and Prives, 2012; Muller and Vousden, 2014; Bykov et al., 2018; Kim and Lozano, 2018…”
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Glutathione S-Transferases in Cancer
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“Because PFKFB3 contains a kinase domain and a phosphatase domain, three human FLAG-tagged PFKFB3 vectors harboring FL (1-520), N-terminal (N, 1–245) and C-terminal (C, 246–520) constructs were constructed to identify the PFKFB3 residues that associated with AGPG.”
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“As the p53 gene is frequently mutated or silenced in human cancer (5,6), most cancer cells have a dysfunctional G1 / S checkpoint and therefore depend on the S and G2 / M checkpoints for survival in response to genotoxic stress (7).”
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“Possible therapies include chemotherapy, radiation, surgery, immunotherapy, targeted therapy, and gene therapy (Wang et al., 2013; Roy and Trinchieri, 2017; Bykov et al., 2018; Senft et al., 2018).”
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“Based on the wisdom of Mother Nature, the development of new cancer medicines, aimed at the correction of the mutant p53 form [96,97], may provide new horizons in cancer treatment.”
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Tang, Q., Su, Z., Gu, W., & Rustgi, A. K. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.11.004 · Cited by 155
“Therefore, p53 mutants that are deficient in Zn2+ binding are reactivated [99].”
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“Although the exact mechanisms of mutp53 reactivation remain to be elucidated, these reactivators have been shown to efficiently induce cell cycle arrest or apoptosis in vitro and in vivo to suppress tumor malignancy and progression [39,53].”
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“, which have been discussed in several reviews.(98,99) Therefore, mutant p53 has been proposed as a preventive and therapeutic target in cancer.”
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“The core region of p53 shows as a tetramer that binds to DNA from two different rotation angles according to the cBioportal database, the TP53 website and the International Agency for Research on Cancer (IARC) TP53 database [50].”
MethodIdentification of a highly lethal V3 + TP53 + subset in ALK + lung adenocarcinoma
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“Besides, compounds that restore wild-type p53 transcriptional activity or reduce mutant p53 levels are currently being developed for the treatment of TP53 mutated tumors.(35) In summary, our study shows that TP53 mutations and V3 are independently associated with enhanced metastatic spread, shorter TKI responses and i…”
BackgroundLiao, H., Long, Y., Han, R., Wang, W., Xu, L., Liao, M., Zhang, Z., Wu, Z., Shang, X., Li, X., et al. (2020) · Clinical and Translational Medicine · doi:10.1002/ctm2.102 · Cited by 92
“It is also noticeable that AUCs for TP53, of which the somatic mutations contribute to human cancers in different ways, 16,17 reached a value at 0.773 using Method 1 (Table S5).”
MethodInfluentialEmerging next-generation sequencing-based discoveries for targeted osteosarcoma therapy
Zhao, J., Dean, D. C., Hornicek, F. J., Yu, X., & Duan, Z. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.01.020 · Cited by 92
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“Increasing p53 activity represents a potential therapeutic target that could offer patients with a range of different tumor types new treatment options (11, 27, 28).”
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“Phase I studies of PRIMA-1, a PRIMA-1 analog associated with cisplatin, have been concluded, and phase II trials are now in development (25, 26).”
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Drugging “undruggable” genes for cancer treatment: Are we making progress?
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Emerging Pathological Engagement of Ferroptosis in Gut Diseases
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“In response to diverse stimuli, P53 is stabilized to mediate metabolic reprogramming, cell cycle arrest, cellular senescence, and even cell death [150].”
DAXX represents a new type of protein-folding enabler
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Targeting oxidative stress-mediated regulated cell death as a vulnerability in cancer
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“…its interaction with MDM2, and acetyl transferases such as CREBBP and KAT5, which activate p53 for specific DNA binding by acetylation [166,167]. p53 can also be directly modified by ROS through the oxidation of cysteine residues, thereby altering its conformation and function and…”
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Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations
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Pharmacological reactivation of p53 in the era of precision anticancer medicine
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“…reveal opportunities for the treatment of tumours carrying mutant TP53 and/or PMp53 with compounds capable of modulating the dynamic equilibrium between p53 conformations by either stabilizing the wild-type conformation or reverting misfolded p53 proteins to the wild-type conformation 56,57 .”
Self-citationTherapeutic vaccines for breast cancer: Has the time finally come?
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“p53MVA Mutations in TP53 gene are present in a majority of solid tumours, resulting in the accumulation of oncogenic and potentially immunogenic p53 protein product within tumour cells [102].”
Deregulation and Targeting of TP53 Pathway in Multiple Myeloma
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Germline risk of clonal haematopoiesis
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COTI-2 reactivates mutant p53 and inhibits growth of triple-negative breast cancer cells
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Venetoclax therapy and emerging resistance mechanisms in acute myeloid leukaemia
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“Mutations in the tumour suppressor gene TP53 are the most frequently observed genetic aberration in cancers [74] and are found in up to 8% of diagnostic AML patients (Table 1) [29].”
BackgroundUSP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells
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Analysis and Interpretation of the Impact of Missense Variants in Cancer
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“The tumor suppressor p53 is one of the most frequently mutated proteins found in cancer [52,53,81].”
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“There are efforts underway to restore the function of mutant p53 or re-introduce wild type p53, and such strategies may be used to complement or potentiate the RiBi stress-inducing agents [63].”
BackgroundHuman MYC G-quadruplex: From discovery to a cancer therapeutic target
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The multiple roles and therapeutic potential of HSP60 in cancer
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“TP53, a well-known tumor suppressor and transcriptional activator or repressor, is the most frequently mutated genes in cancer [9], mutation of which allows tumor evasion and induces rapid tumor progression [10].”
Metadata
- Authors
- Bykov, V. J. N., Eriksson, S. E., Bianchi, J., & Wiman, K. G.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Wiman, Klas G.
- Venue
- Nature Reviews Cancer
- Published
- 2017-12-15
- Volume
- 18
- Issue
- 2
- Pages
- 89-102
- ISSN
- 1474-175X (ISSN-L)
- 1474-1768
- 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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