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Pharmacological reactivation of p53 in the era of precision anticancer medicine

Nature Reviews Clinical Oncology volume 21, pages 106–120 (2024)Cite this article

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Abstract

p53, which is encoded by the most frequently mutated gene in cancer, TP53, is an attractive target for novel cancer therapies. Despite major challenges associated with this approach, several compounds that either augment the activity of wild-type p53 or restore all, or some, of the wild-type functions to p53 mutants are currently being explored. In wild-type TP53 cancer cells, p53 function is often abrogated by overexpression of the negative regulator MDM2, and agents that disrupt p53–MDM2 binding can trigger a robust p53 response, albeit potentially with induction of p53 activity in non-malignant cells. In TP53-mutant cancer cells, compounds that promote the refolding of missense mutant p53 or the translational readthrough of nonsense mutant TP53 might elicit potent cell death. Some of these compounds have been, or are being, tested in clinical trials involving patients with various types of cancer. Nonetheless, no p53-targeting drug has so far been approved for clinical use. Advances in our understanding of p53 biology provide some clues as to the underlying reasons for the variable clinical activity of p53-restoring therapies seen thus far. In this Review, we discuss the intricate interactions between p53 and its cellular and microenvironmental contexts and factors that can influence p53’s activity. We also propose several strategies for improving the clinical efficacy of these agents through the complex perspective of p53 functionality.

Key points

  • A range of cell-intrinsic and cell-extrinsic factors can affect the activity of p53, as exemplified by the regulation of p53 degradation by MDM2–MDM4 (cell-intrinsic), and the effects of cytokine-producing cancer-associated fibroblasts or a metabolite-producing microbiota on p53 levels and function (cell-extrinsic).

  • Activation of wild-type p53 in non-malignant cells can cause substantial toxicity, given that p53 levels are normally tightly controlled by MDM2–MDM4 and that unbridled p53 activity can trigger irreversible cellular demise.

  • The heterogeneity of cancer-driving TP53 mutations and the existence of tumours with wild-type TP53 that nonetheless lack functional p53 creates various forms of p53 dysfunction, which challenges the development of effective p53-reactivating therapies for large groups of patients.

  • Owing to the heterogeneous effects of different TP53 variants and p53 protein aberrations, effective therapies capable of restoring wild-type p53 function will most probably require personalization according to the specific p53 functionality of each patient.

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Fig. 1: Domain structure of the p53 protein and the spectrum of TP53 mutations in cancer.
Fig. 2: The clonal evolution of TP53-mutant tumours.
Fig. 3: Complex interplay between TP53-mutant cancer cells and their microenvironment.
Fig. 4: Therapeutic strategies for wild-type TP53 cancers.
Fig. 5: Therapeutic strategies for TP53-mutant cancers.
Fig. 6: A practical flowchart for assessing TP53 status and p53 functionality in patients with cancer.

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Acknowledgements

This work was supported by grants from the European Research Council (advanced ERC grant no. 694825-TRANSREAD), the Swedish Research Council (VR 2017-01509; 2021-02064), the Swedish Cancer Fund (Cancerfonden 18 0774; 21 1473 Pj 01 H), the Swedish Childhood Cancer Fund (Barncancerfonden PR2020-0042) and Radiumhemmets Forskingsfonder (201383). We apologize to all authors whose work could not be referenced owing to limited space.

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  1. Karolinska Institutet, Department of Oncology-Pathology, Stockholm, Sweden

    Amos Tuval, Charlotte Strandgren, Angelos Heldin, Mireia Palomar-Siles & Klas G. Wiman

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All authors researched data for this manuscript. A.T. and K.G.W. made a substantial contribution to discussions of content. All authors wrote the manuscript and edited and/or reviewed the manuscript prior to submission.

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Correspondence to Klas G. Wiman.

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K.G.W. has received research funding from, is a cofounder and shareholder of, and has previously received a salary from Aprea Therapeutics, a company that develops p53-based cancer therapies including eprenetapopt. The other authors declare no competing interests.

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Tuval, A., Strandgren, C., Heldin, A. et al. Pharmacological reactivation of p53 in the era of precision anticancer medicine. Nat Rev Clin Oncol 21, 106–120 (2024). https://doi.org/10.1038/s41571-023-00842-2

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