Anticancer therapeutic strategies for targeting mutant p53-Y220C

Abstract

The tumor suppressor p53 is a transcription factor with a powerful antitumor activity that is controlled by its negative regulator murine double minute 2 (MDM2, also termed HDM2 in humans) through a feedback mechanism. At the same time TP53 is the most frequently mutated gene in human cancers. Mutant p53 proteins lose wild-type p53 tumor suppression functions and acquire new oncogenic properties among which are deregulated cell proliferation, increased chemoresistance, disruption of tissue architecture, promotion of migration, invasion and metastasis, and several other pro-oncogenic activities. The oncogenic p53 mutation Y220C, which accounts for over 100 000 cancer cases per year, creates an extended surface crevice in the DNA-binding domain destabilizing p53 and causing its denaturation and aggregation. This cavity can accommodate stabilizing small molecules that have therapeutic value. The development of suitable small-molecule stabilizers is one of the therapeutic strategies for reactivating the Y220C mutant protein. In this review we summarize approaches that target p53-Y220C, including reactivating this mutation with small molecules that bind Y220C hydrophobic pocket and developing immunotherapies as the goal of near future, which could target tumor cells that express the p53- Y220C neoantigen.