Killing by Proximity

p53 tumor suppressor evolved as the critical player in navigating the response to environmental stresses such as DNA, or oxidative damage and drives the cell fate by governing the live and death decision. The p53 protein is encoded by the most commonly mutated gene in human cancers. TP53 gene mutations are associate with worse prognosis and refractory and relapse disease. The most prevalent mutations are of the missense type and often lead to disruption of DNA binding capacity. In healthy cells, p53 protein is tightly regulated by its E3 ubiquitin ligase, MDM2 (HDM2), it’s own transcription target. Mutant p53 therefore escapes the regulation by the negative feedback loop and is often found upregulated in cancer cells. The efforts to exploit mutant p53 for precision medicine has been ongoing in the last decade, yet not successful. One way to target TP53-mutant cancers would be by proximity, where abundant mutp53 protein serves as a molecular glue for a toxin inhibiting essential gene. The strategy might still require the adjustments but emerges as promising strategy for precision oncology.