The Development of p53-Targeted Therapies for Human Cancers

Abstract

p53 plays a critical role in tumor suppression and is the most frequently mutated gene in human cancers. Most p53 mutants (mutp53) are missense mutations and are thus expressed in human cancers. In human cancers that retain wtp53, the wtp53 activities are downregulated through multiple mechanisms. For example, the overexpression of the negative regulators of p53, MDM2/MDMX, can also efficiently destabilize and inactivate wtp53. Therefore, both wtp53 and mutp53 have become promising and intensively explored therapeutic targets for cancer treatment. Current efforts include the development of small molecule compounds to disrupt the interaction between wtp53 and MDM2/MDMX in human cancers expressing wtp53 and to restore wtp53-like activity to p53 mutants in human cancers expressing mutp53. In addition, a synthetic lethality approach has been applied to identify signaling pathways affected by p53 dysfunction, which, when targeted, can lead to cell death. While an intensive search for p53-targeted cancer therapy has produced potential candidates with encouraging preclinical efficacy data, it remains challenging to develop such drugs with good efficacy and safety profiles. A more in-depth understanding of the mechanisms of action of these p53-targeting drugs will help to overcome these challenges.

Keywords: DNA-binding activity; MDM2/MDMX; gain-of-function; p53 mutation; targeted therapy.

Figure 1

Summary of the strategies to target wtp53 and mutp53 in human cancers. For activating wtp53, drug development has been focused on strategies to disrupt the interaction between p53 and its negative regulators MDM2/MDMX. For human cancers expressing mutant p53, drug development has been focused on strategies to restore wild-type p53 activities to mutp53. In addition, drugs to eradicate mutp53 and induce synthetic lethality of tumor cells expressing p53 mutants have also been explored.