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

Key Points 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. 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. 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. We propose a novel, simplified classification system to categorize the various functional classes of p53 mutants for use in clinical oncology. 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. 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. TP53 , encoding the tumour-suppressor p53, is the most frequently mutated gene across all human cancers. Similar to other transcription factors, p53 has proved notoriously difficult to target therapeutically; to date, no p53-targeted therapies have entered the clinic. The diversity of TP53 mutations, which can be categorized across a spectrum of different functional classes, is increasingly recognized as an additional challenge to developing p53-directed treatments. Herein, Kanaga Sabapathy and David Lane review this 'rainbow of p53 mutants', and discuss the implications for anticancer therapies targeting p53 or directed by TP53 status. 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 res