Therapeutic Targeting of p53

Categorization of the major classes of p53 mutants based on their functionality in tumour suppression and response to therapy

An article published on 26 September 2017 in the Nature Reviews Clinical Oncology underlines that increasing knowledge of mutant forms of p53 supports the hypothesis that not all p53 mutants have equivalent cellular effects. The authors elaborate that the mutations across TP53 form a 'rainbow of mutants', necessitating the use of diverse strategies to selectively target specific classes of mutation.

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. However, the increasing knowledge of mutant forms of p53 supports the hypothesis that not all p53 mutants have equivalent cellular effects.

In their article the authors propose a categorization of the major classes of p53 mutants based on their functionality in tumour suppression and response to therapy. They underline on emerging picture 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 knowledge of TP53 mutations in developing selective therapeutic options, and in facilitating clinical decision-making is discussed in the article in more details.

Reference

Sabapathy S, Lane D. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nature Reviews Clinical Oncology 2017;Sep 26. doi: 10.1038/nrclinonc.2017.151. [Epub ahead of print].