New therapeutic strategies to treat human cancers expressing mutant p53 proteins

Giovanni Blandino, Silvia Di Agostino

The tumor suppressor p53 plays a critical role to preserve DNA fidelity from diverse insults through the regulation of cell-cycle checkpoints, DNA repair, senescence and apoptosis. The TP53 is the most frequently inactivated gene in human cancers. This leads to the production of mutant p53 proteins that loose wild-type p53 tumor suppression functions and concomitantly acquire new oncogenic properties among which deregulated cell proliferation, increased chemoresistance, disruption of tissue architecture, promotion of migration, invasion and metastasis and several other pro-oncogenic activities. Mouse models show that the genetic reconstitution of the wild type p53 tumor suppression functions rescues tumor growth. This strongly supports the notion that either restoring wt-p53 activity or inhibiting mutant p53 oncogenic activity could provide an efficient strategy to treat human cancers. In this review we briefly summarize recent advances in the study of small molecules and compounds that subvert oncogenic activities of mutant p53 protein into wt-p53 tumor suppressor functions. We highlight inhibitors of signaling pathways aberrantly modulated by oncogenic mutant p53 proteins as promising therapeutic strategies. Finally, we consider the clinical applications of compounds targeting mutant p53 and the use of currently available drugs in the treatment of tumors expressing mutant p53 proteins.