Translational advances in p53 targeted cancer therapy from molecular mechanisms to clinical application

The p53 tumor suppressor is among the most valid oncogenes targets. Although translation of p53-based therapies has had inconsistent results regardless of strong preclinical validation, it remains evident that a clear gap exists between the biological rationale and therapeutic durability. This review is a critical assessment of p53-directed strategies, like mutant p53 reactivation, activation of suppressed wild-type p53 via MDM2/MDMX inhibition, gene replacement strategies, and targeting the loss of p53. This review is not to enlist therapeutic agents or pathways, but instead to evaluate the constraints for translation, i.e. pathway dependency, and limitations on the therapeutic window, and trial design mismatch, that have chosen clinical outcomes. Experiences of failures of late-stage clinical trials show that p53 targeting/restoration is often not sufficient to produce a lasting tumor remission. The future directions are in allele-specific mutant targeting, patient stratification based on biomarkers, adaptive trial design, and rational combination strategies that increase the level of stress beyond tolerable levels. The structurally druggable alleles are only a small minority of TP53-mutant disease, with the Y220C hotspot accounting for approximately 1.8% of TP53-mutant tumors and interim phase II data for rezatapopt showing objective responses of 33–34% with a median duration of response of 6.2–7.6 months. In contrast, pan-mutant agents are expected to have a strong effect on redox modulation as well as on structural refolding, accounting for the fact that it gets diluted in the unselected cohorts. New proximity inducing modalities, such as PROTAC degraders of mutants, molecular glues and p53 mRNA nanotherapy, expand the therapeutic toolbox beyond refolding, and proof that p53 restoration remodels the tumor immune microenvironment also offers a rationale for combination with immune checkpoint blockade.