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Nat Rev Clin Oncol. 2018 Jan;15(1):13-30. doi: 10.1038/nrclinonc.2017.151. Epub 2017 Sep 26.

Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others.

Author information

1
Laboratory of Molecular Carcinogenesis, Division of Cellular & Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
2
Department of Biochemistry, National University of Singapore (NUS), 8 Medical Drive, Singapore 117597, Singapore.
3
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
4
Institute of Molecular and Cellular Biology, 61 Biopolis Drive, Singapore 138673, Singapore.
5
p53 Laboratory (p53Lab), Agency for Science, Technology, and Research (A*STAR), Singapore 138648, Singapore.

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.

PMID:
28948977
DOI:
10.1038/nrclinonc.2017.151
[Indexed for MEDLINE]

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