Therapeutic avenues to target mutant p53
Mutant p53 proteins are highly expressed in many cancers, making them extremely attractive targets for therapy. Strategies have focused on destabilization or inactivation of mutant p53, or reactivation of wild-type function in the mutant p53 protein. The latter strategy is difficult to achieve, but particularly appealing in light of mouse models showing that the activation of wild-type p53 in established tumours can lead to efficient tumour regression89. Drugs that inhibit aggregation of certain p53 mutants have also been described.
Destabilization of mutant p53 has been addressed mainly by targeting heat shock proteins through histone deacetylases to rescue MDM2-dependent degradation of mutant p53 (refs 91,92), whereas disruption of mutant p53 function may be achieved by preventing its interaction with other transcription factors. To this end, the molecule RETRA has been shown to inhibit the mutant p53–p73 interaction and to restore p73 function. A number of compounds or peptides that result in the reactivation of wild-type function in mutant p53 have also been described[94,95,96,97,98,99,100,101]. Some of these compounds bind to grooves in the mutant p53 proteins and readjust the folding into a wild-type conformation, but for many the exact mechanism of function is unknown. In some cases, the reactivating compound appears to be specific for a certain mutation (Y220C)or for a group of mutations (conformational mutants)[94,98,99,100]. Peptides corresponding to the C-terminus of p53 have been shown to restore apoptosis induction by both structural and contact p53 mutants[96,102]. This is interesting given the importance of the C-terminus for mutant p53 function[40,50,103], but further studies are necessary to explore the mechanisms involved.
A more accessible approach may be to target the downstream pathways mediating mutant p53 activity. Mutant p53 has multiple functions — so it is unclear how effective the modulation of only one of these will be. Nevertheless, the ability of mutant p53 to engage in signalling pathways for which established, clinically approved drugs are already available (such as EGFR, MET and cholesterol synthesis pathways) gives hope that rapid progress may be made in translating such approaches into the clinic.
p53 mutations in cancer