The TP53 tumour suppressor gene is mutated in close to half of all human tumours
Most TP53 mutations are missense mutations leading to single amino acid substitutions in the p53 protein
Small molecules that reactivate missense-mutant p53 and induce tumour cell death have been identified by various approaches
Two mutant-p53-reactivating compounds are being tested in clinical trials
Reactivation of nonsense-mutant TP53 by induction of translational readthrough has been demonstrated with aminoglycoside antibiotics
Novel anticancer drugs that reactivate mutant p53 should have wide clinical applicability
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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K.G.W. is supported by grants from the Swedish Cancer Foundation (Cancerfonden), the Swedish Medical Research Council (VR), the Swedish Childhood Cancer Foundation (Barncancerfonden), Radiumhemmets Forskningsfonder, Karolinska Institutet, the Wallenberg Foundation (KAW), the European Research Council (ERC) and Aprea Therapeutics AB. J.B. is supported by Svenska Sällskapet för Medicinsk Forskning (SSMF). The authors thank L. Abrahmsen, R. Tell and M. von Euler, Aprea Therapeutics AB, for valuable comments on the manuscript.
K.G.W. and V.J.N.B. are cofounders and shareholders of Aprea Therapeutics AB, a company that develops p53-based cancer therapy, including APR-246. K.G.W. is a member of its Clinical Advisory Board. Research in the K.G.W. laboratory has financial support from Aprea Therapeutics AB. K.G.W. has received a salary from Aprea Therapeutics AB. The other authors declare no competing interests.
A mode of regulated cell death that requires iron and that depends on lipid peroxidation.
- Missense mutations
Mutations that give rise to an amino acid substitution in the protein.
- Nonsense mutations
Mutations that create a premature termination codon and cause expression of a truncated protein.
- Translational readthrough
A process in which the ribosome continues translation through a premature termination codon in an mRNA, leading to synthesis of full-length protein.
- Law of mass action
A law that states that the rate of a chemical reaction is directly proportional to the product of the masses or concentrations of the reactants.
- Michael acceptors
Organic molecules with an unsaturated carbon–carbon double bond coupled to an electron-withdrawing group.
- Michael addition
The conjugate addition of a Michael acceptor to a nucleophile.
- Pegylated doxorubicin
A formulation of the chemotherapeutic drug doxorubicin in which the drug is packed in liposomes, allowing improved longevity and drug delivery to tumour tissue.
- Response Evaluation Criteria in Solid Tumours 1.1
(RECIST1.1). Defined rules for assessment of the treatment response of patients with cancer. RECIST1.1 differs from RECIST with regard to several criteria, including the number of lesions to be assessed and the assessment of pathological lymph nodes.
- Gynecologic Cancer InterGroup
(GCIG). An organization with the aim of promoting high-quality clinical trials in order to improve outcomes for patients with gynaecological cancer.
- Nucleophilic aromatic substitution
A substitution reaction in which a nucleophile replaces a leaving aromatic group.
- Imino group
A functional group containing a carbon–nitrogen double bond.
- Nonsense-mediated mRNA decay
(NMD). A pathway that selectively degrades mRNAs with premature termination codons.
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Bykov, V., Eriksson, S., Bianchi, J. et al. Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer 18, 89–102 (2018). https://doi.org/10.1038/nrc.2017.109
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