As the most frequently mutated protein across cancers, the tumor suppressor protein p53 is inactivated by the most extensive array of different mutations. Targeting a frequent p53 mutant with the reactivator rezatapopt, recent findings published in the New England Journal of Medicine mark an encouraging step toward clinical utility.

P1, N=14, Recruiting, PMV Pharmaceuticals, Inc | Not yet recruiting --> Recruiting

Findings from a phase I study show that the p53 reactivator rezatapopt is safe and can elicit responses in patients with a range of solid tumors containing the Y220C mutation. Although the drug was ineffective in tumors with KRAS mutations, and whether the strategy can be applied to more common missense mutations remains unclear, the findings offer proof of concept for p53 reactivation.

The Y220N mutant, despite exhibiting high-nanomolar affinity for rezatapopt and substantial stabilization, did not show noticeable effects in cells at the concentrations tested, as rezatapopt binding resulted in only partial compensation for the mutation-induced loss of stability, for which we provide a structural explanation. Our data suggest that the development of clinical pan-Y220C/N/S reactivators, which could benefit an additional 10,000 patients per year, is challenging but not impossible.

In this phase 1 study involving heavily pretreated patients, the most common adverse events associated with rezatapopt were nausea and vomiting. Antitumor activity occurred across multiple tumor types, providing proof of concept for p53 reactivation. (Funded by PMV Pharmaceuticals; PYNNACLE ClinicalTrials.gov number, NCT04585750.).

A combination of defactinib and the MDM2 inhibitors showed that nutlin-3a showed synergistic/additive effects in wild-type and antagonistic effects in mutated TP53 cells, whereas RITA retained synergistic activity in mutated TP53 cells. These results suggest that the therapeutic success of combined FAK and MDM2 inhibition in mesothelioma depends on the precise matching of MDM2 inhibitors with the TP53 genotypes, and highlight the need for genotype-based selection of MDM2 inhibitors.

Therapeutic approaches include Mtp53 reactivators (e.g., APR-246, PC14586), degraders, synthetic lethal strategies, and neoantigen vaccines. Its combination with pembrolizumab (NCT04383938) demonstrated acceptable safety (immune-related adverse events in ∼12%) but limited efficacy, underscoring the need for biomarker-guided, precision-based combinations. Thus, a multidimensional biomarker platform is urgently needed-one integrating TP53 mutation subtypes (e.g., R175H vs. nonsense mutations), dynamic ctDNA monitoring (VAF ≥ 0.01%), tumor immune microenvironment (TIME) features (e.g., TILs, MDSCs), and spatial multi-omics-to enable precise molecular stratification and personalized intervention in Mtp53-driven cancers.

Overall, our findings indicate that neither CP31398 nor FG-CP31398 binds directly to p53 but instead interacts with an unidentified target. While unsuitable for p53 imaging, these radiotracers may serve as valuable tools to unravel the controversial mechanism of action of CP31398.

Small-molecule correctors, statins, Hsp90 inhibitors, and new drugs like Eprenetapopt and COTI-2 are among the therapeutic options proposed. Challenges such as medication resistance, side effects, and the chemical complexity of p53 pathways are also addressed, emphasizing the importance of ongoing research. This review contributes to our understanding of TP53-targeted cancer medicines, offering hope for more innovative treatments with improved outcomes.

P1, N=14, Not yet recruiting, PMV Pharmaceuticals, Inc

Compared with the inhibitor group, the serum level of IL-6, the contents of 4-HNE and MDA, and protein expression of p53 in colonic tissue in the activator group were elevated (P<0.05), while the body weight, the contents of SOD and GSH, and protein expression of GPX4 in colonic tissue were reduced (P<0.05). Moxibustion at "Tianshu" (ST25) could alleviate intestinal inflammation in CD mice, possibly by downregulating the protein expression of p53, enhancing the activity of the SLC7A11/GSH/GPX4 pathway, reducing the production of lipid peroxides, maintaining intestinal iron homeostasis, and reducing colonic ferroptosis.

These findings clarified that CP-31398 could elevate the transcriptional function of p53 probably by modulating the phase behavior. The study provided new insights into the regulation mechanism of p53 and potential therapeutic avenues for cancer.