Mutant p53 as a Therapeutic Target: The Report of Its Death Was an Exaggeration

TP53 is the most frequently mutated gene in human cancers. Many studies have reported oncogenic gain of function by mutant p53 and suggested that mutant p53 is a potential therapeutic target. In striking contrast, a recent approach relying on CRISPR-mediated mutagenesis led to the conclusion that mutant p53 removal in tumors had no therapeutic value. However, experimental limitations likely affected this study, including the difficulty of recapitulating the events leading to mutant p53 gain of function in cancer cell lines. Furthermore, a low statistical power may have masked the impact of mutant p53 removal in organoid-derived tumors. Independently, two studies focusing on the human hotspot mutant TP53^Y220C and its murine homolog Trp53^Y217C recently provided compelling evidence that mutant p53 can be a valid therapeutic target. Drugs designed to stabilize the mutant protein and restore wild-type p53 functions, or to inhibit the inflammatory effects associated with mutant p53, appear particularly promising.