It elaborates on the structure and function of p53 and its mutation-induced carcinogenic mechanisms, then focuses on analyzing the research history and clinical translation status of small-molecule drugs (e.g., APR-246), discusses the application prospects of gene therapy and immunotherapy strategies, and introduces emerging therapies based on CRISPR and PROTAC technologies. By integrating the latest research findings, this article aims to provide theoretical basis and directional guidance for the precise development and clinical translation of p53-targeted drugs.

This paper reports genetic variants in 20 CLs as well as the results of the assessment on whether those variants may help predict response or resistance to certain drug families. With a few exceptions, genetic alteration frequency in CCCLs, conducted in the same analytical batches, compares favorably with published patient data. Results need confirmation in independent larger studies both in CLs and in clinical settings.

Moreover, treatment with RITA, a small-molecule activator of TRP53, disrupted the TRP53-LC3 interaction, stabilized TRP53 levels, and protected ahNSCs from ACD, ultimately preventing CRS-induced cognitive impairment in the hippocampus. These findings identify TRP53 as a key negative regulator of ACD in ahNSCs and suggest that TRP53-stabilizing small molecules could represent a novel class of antidepressant therapies by preserving AHN.

This study demonstrates that p53-specific effects of APR-246 are only observable in a narrow dosing window, under a specific set of conditions. Collectively, our results highlight the limitation of APR-246 as a p53-rescuing drug because of its overwhelming off-target effects on the redox system at doses that are sufficient to induce ferroptosis but insufficient to rescue mutant p53.

These findings support a rational therapeutic strategy that exploits oxidative genomic instability and synthetic lethality via HR pathway disruption, offering a promising combination therapy for managing mut/delp53 MCL.

Combining eprenetapopt with carboplatin shows promising preclinical efficacy by enhancing cytotoxicity in olaparib-resistant models and demonstrating synergistic interaction; these data support the combination as a potential strategy to mitigate PARPi resistance and carboplatin cross-resistance in TP53 mutant HGSOC and TNBC cell lines. Although further studies are needed to elucidate the molecular mechanisms underlying the synergistic effect, here we point out the combination of eprenetapopt and carboplatin as a potential therapeutic strategy to address olaparib resistance in HGSOC and TNBC patients.

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.