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  • Review Article
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Translating p53-based therapies for cancer into the clinic

Nature Reviews Cancer volume 24, pages 192–215 (2024)Cite this article

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Abstract

Inactivation of the most important tumour suppressor gene TP53 occurs in most, if not all, human cancers. Loss of functional wild-type p53 is achieved via two main mechanisms: mutation of the gene leading to an absence of tumour suppressor activity and, in some cases, gain-of-oncogenic function; or inhibition of the wild-type p53 protein mediated by overexpression of its negative regulators MDM2 and MDMX. Because of its high potency as a tumour suppressor and the dependence of at least some established tumours on its inactivation, p53 appears to be a highly attractive target for the development of new anticancer drugs. However, p53 is a transcription factor and therefore has long been considered undruggable. Nevertheless, several innovative strategies have been pursued for targeting dysfunctional p53 for cancer treatment. In mutant p53-expressing tumours, the predominant strategy is to restore tumour suppressor function with compounds acting either in a generic manner or otherwise selective for one or a few specific p53 mutations. In addition, approaches to deplete mutant p53 or to target vulnerabilities created by mutant p53 expression are currently under development. In wild-type p53 tumours, the major approach is to protect p53 from the actions of MDM2 and MDMX by targeting these negative regulators with inhibitors. Although the results of at least some clinical trials of MDM2 inhibitors and mutant p53-restoring compounds are promising, none of the agents has yet been approved by the FDA. Alternative strategies, based on a better understanding of p53 biology, the mechanisms of action of compounds and treatment regimens as well as the development of new technologies are gaining interest, such as proteolysis-targeting chimeras for MDM2 degradation. Other approaches are taking advantage of the progress made in immune-based therapies for cancer. In this Review, we present these ongoing clinical trials and emerging approaches to re-evaluate the current state of knowledge of p53-based therapies for cancer.

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Fig. 1: The two facets of p53 activity in cancer.
Fig. 2: Targeting mutant p53.
Fig. 3: Reactivation of wild-type p53.
Fig. 4: Wild-type and mutant p53 modulation of the immune response to tumours.
Fig. 5: p53 activated by MDM2 inhibition triggers a viral mimicry response and sensitizes tumours to immune checkpoint blockade therapy.
Fig. 6: p53-based immunotherapy approaches.

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Acknowledgements

This study has been supported by Swedish Cancer Society grants to G.S. and S.P., grants from the Swedish Research Council to G.S. and from the Swiss Bridge Foundation to S.P., as well as support from the Karolinska Institutet.

Author information

Authors and Affiliations

  1. Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden

    Sylvain Peuget & Galina Selivanova

  2. Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Xiaolei Zhou

  3. Institute of Materials Science and Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

    Xiaolei Zhou

Authors
  1. Sylvain Peuget
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  2. Xiaolei Zhou
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  3. Galina Selivanova
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Contributions

All authors researched data for the article. S.P. and G.S. contributed substantially to discussion of the content. All authors wrote the article. S.P. and G.S. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Galina Selivanova.

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Competing interests

G.S. is a co-founder of Aprea Therapeutics AB. All other authors declare no competing interests.

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Related links

Genomics of Drug Sensitivity in Cancer database: https://www.cancerrxgene.org/

PANDA (p53 and arsenic) project: http://www.rescuep53.net

PMV Pharma: https://www.pmvpharma.com/pipeline/#PC14586

The TP53 database: https://tp53.isb-cgc.org

Glossary

Antimony

A metalloid chemical element with the symbol Sb and atomic number 51. Antimony compounds have been known since ancient times and were powdered for use as medicine and cosmetics, often known by the Arabic name kohl.

BCL-2 homology 3 (BH3) mimetics

Compounds that bind to pro-survival BCL-2 proteins and neutralize them, similar to pro-apoptotic BH3-only proteins.

Chemoprotective agents

Types of drug that help to protect healthy tissue from some of the side effects caused by certain anticancer drugs.

Covalent modifiers

Types of drug that bind by forming a chemical bond with its target. This covalent binding can improve the selectivity of the drug for a target with complementary reactivity and result in increased binding affinities due to the strength of the covalent bond formed.

Creatinine

A chemical waste product of creatine, removed from the body by the kidneys.

CRISPR adenine base-editing system

A system that combines the sequence-identification capabilities of the CRISPR–Cas9 system with base editing by deaminase enzymes, which convert A•T base pairs to G•C pairs (adenine editor) or C•G base pairs to T•A pairs (cytosine editor) without the intentional generation of a DNA double-strand break.

Diabody

Bispecific antibody fragments that have two antigen-binding Fv domains.

Endogenous retroviruses

(ERVs). Endogenous viral elements in the genome that closely resemble and can be derived from retroviruses.

Febrile neutropenia

Febrile neutropenia is the presence of fever in a neutropenic patient. It is the most common life-threatening complication of cancer therapy and is considered an oncological emergency.

Hypomorphic

A reduction in gene or protein activity as a result of mutation.

Insertional mutagenesis

The creation of mutations in DNA by the addition of one or more base pairs. Such insertional mutations can occur naturally, mediated by viruses or transposons, or can be artificially created.

Intra-S checkpoint

A cascade of signalling events that puts the S phase on hold until the DNA damage is repaired.

Mevalonate pathway

Accounts for the conversion of acetyl-CoA into isopentenyl 5-diphosphate, the versatile precursor of polyisoprenoid metabolites and natural products.

Missense mutations

Point mutations in which a single-nucleotide change result in a codon that encodes a different amino acid. It is a type of nonsynonymous substitution.

Nonsense-mediated mRNA decay

Degradation of mRNAs with translation termination codons in abnormal contexts.

Nonsense mutations

Point mutations that result in a premature stop codon, or a nonsense codon in the transcribed mRNA, leading to a truncated and nonfunctional protein product.

Repetitive transposable elements

(RTEs). Highly repetitive DNA sequences in the human genome that are the relics of previous retrotransposition events.

Replication stress

The state of a cell whose genome is exposed to various stresses during DNA replication and can result in a stalled replication fork.

Secondary-site suppressor mutations

Secondary mutations in a site different from the original mutation that alleviate or revert the phenotypic effects of an already existing mutation.

Senescence-associated secretory phenotype

(SASP). A phenotype associated with senescent cells in which those cells secrete high levels of inflammatory cytokines, immune modulators, growth factors and proteases.

Solvent accessibility

A key feature of proteins for determining their folding and stability, computed from protein structures with different algorithms.

Stapled peptide

A stapled peptide is a short peptide, typically in an α-helical conformation, that is constrained by a synthetic brace. The staple is formed by a covalent linkage between two amino acid side chains.

SV40 large T-antigen

A hexamer protein that is a dominant-acting oncoprotein derived from the polyomavirus SV40, which binds to and inhibits p53 and RB to allow virus replication.

Temperature-sensitive mutants

Types of mutant with an altered or loss of function at higher or physiological temperatures but have normal function of the protein (or gene) at low temperatures.

Thrombocytopenia

A condition that occurs when the platelet count in blood is too low.

Transactivation

The induction of an increased rate of gene expression.

Tumour inflammation signature

(TIS). An 18-gene signature that measures a pre-existing but suppressed adaptive immune response. It comprises immune genes that have been shown to enrich for response to immune checkpoint inhibition.

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Peuget, S., Zhou, X. & Selivanova, G. Translating p53-based therapies for cancer into the clinic. Nat Rev Cancer 24, 192–215 (2024). https://doi.org/10.1038/s41568-023-00658-3

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