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Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others
Abstract
TP53, which encodes the tumour-suppressor protein p53, is the most frequently mutated gene across all cancer types. The presence of mutant p53 predisposes to cancer development, promotes the survival of cancer cells, and is associated with ineffective therapeutic responses and unfavourable prognoses. Despite these effects, no drug that abrogates the oncogenic functions of mutant p53 has yet been approved for the treatment of cancer. Current investigational therapeutic strategies are mostly aimed at restoring the wild-type activity of mutant p53, based on the assumption that all p53 mutants are functionally equal. Our increasing knowledge of mutant forms of p53, however, supports the antithetical hypothesis that not all p53 mutants have equivalent cellular effects; hence, a judicious approach to therapeutic targeting of mutant p53 is required. In this Review, we propose a categorization of the major classes of p53 mutants based on their functionality in tumour suppression and response to therapy. The emerging picture is that the mutations across TP53 form a 'rainbow of mutants', with varying degrees of functionality and different pathobiological consequences, necessitating the use of diverse therapeutic strategies to selectively target specific classes of mutation. The utility of this knowledge of TP53 mutations in developing selective therapeutic options, and in facilitating clinical decision-making is discussed.
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From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [95]
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Metadata
- Authors
- Sabapathy, K., & Lane, D. P.
- Affiliations
- National University of Singapore (SG)
- Agency for Science, Technology and Research (SG)
- Corresponding author
- Sabapathy, Kanaga
- Lane, David P.
- Venue
- Nature Reviews Clinical Oncology
- Published
- 2017-09-26
- Volume
- 15
- Issue
- 1
- Pages
- 13-30
- ISSN
- 1759-4774 (ISSN-L)
- 1759-4782
- OpenAlex
- W2759444489
- Cited by
- 517
- References
- 178
- Citations by year
- 2026: 40 · 2025: 67 · 2024: 74 · 2023: 89 · 2022: 57 · 2021: 64 · 2020: 53 · 2019: 41 · 2018: 26 · 2017: 3
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation Singapore
- National Medical Research Council
- 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 › Cancer Research › Cancer Mechanisms and Therapy
- Keywords
- TP53 mutation, mutant p53, p53-targeted therapy, tumour suppressor, cancer therapy resistance, prognostic factors
- MeSH terms
- Humans, Mutation, Neoplasms, Genes, p53
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