Key Points
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Mutations in TP53 (encoding the tumour-suppressor protein p53) are the most common genetic lesions found in cancers, and contribute to cancer development, progression, metastasis, and resistance to therapy.
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The results of decades of research provide detailed insights into the functional consequences of TP53 mutations; however, this knowledge has not been fully exploited in the clinic, owing to difficulties in drugging mutant p53.
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Mutations in TP53 have traditionally been considered functionally equivalent, but an increased understanding of the effects of distinct mutations on p53 activity has led to the recognition of a 'rainbow of mutants' with differing properties.
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We propose a novel, simplified classification system to categorize the various functional classes of p53 mutants for use in clinical oncology.
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These categories are predicated on the location of the mutation within the N-terminal, DNA-binding, or oligomerization domain, as well as the often context-dependent effects of the mutation on p53 function: complete or partial loss of function, a dominant-negative effect, and/or gain-of-function properties.
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Optimal targeting of these functionally variant categories of mutant p53 requires mutation-specific approaches, ranging from restoring wild-type activity to the mutant protein, to degradation of mutant p53.
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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Acknowledgements
We thank the National Medical Research Council of Singapore and the National Research Foundation of Singapore for funding support to K.S., and the Agency for Science, Technology, and Research (A*STAR), Singapore, for funding support to D.P.L.
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K.S. researched data for the article and wrote the manuscript. Both authors contributed to discussions of content and reviewed/edited the manuscript before submission.
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Sabapathy, K., Lane, D. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol 15, 13–30 (2018). https://doi.org/10.1038/nrclinonc.2017.151
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DOI: https://doi.org/10.1038/nrclinonc.2017.151
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