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.

Functional modeling confirmed these double mutants eliminate p53 reactivation and target gene induction by rezatapopt. These findings establish a molecular framework for resistance to p53 Y220C reactivators and inform strategies to overcome resistance with next-generation agents.

Furthermore, we will demonstrate the effectiveness of PRIMA-1 at arresting xenograft growth in an animal model and go on to show that the PRIMA-1 analog APR-246 effectively restores wtp53 tumor suppressor activity in TNBC cells. A brief overview of current clinical trials aimed at reactivating p53 to treat certain cancers is provided. Finally, we discuss the possible use of naturally occurring compounds, which are generally non-toxic, to reactivate mutant p53 and control TNBC progression.

Here, we report the rational design of CuF16@246, an acid-responsive, dual-functional copper-based nanocoordination polymer that integrates Cu2+ and the p53 reactivator eprenetapopt (APR-246) within a single perfluorosebacic acid (PFSEA)-coordinated framework to synergistically induce cuproptosis and reverse tumor metabolic reprogramming...In vitro and in vivo studies demonstrate that CuF16@246 exhibits more efficient cellular uptake, more potent cytotoxicity, and more significant tumor growth inhibition than individual treatments, without inducing hemolysis or major organ toxicity. This work establishes a dual-functional strategy that combines metabolic reprogramming with sensitized cuproptosis, providing a promising framework for developing advanced copper-based nanomedicines for the treatment of mut-p53-positive cancers.

Specifically, MRD negativity after cycle 12 strongly predicted OS (33.9 vs 20.4 months; P=.005) and EFS (33.9 vs 10.1 months; P=.004) with a trend for RFS (32.6 vs 13.5 months; P=.06). TP53 MRD was strongly predictive of outcomes, supporting incorporation of this assay in future novel strategies.

Moreover, PDK1 inhibition increased the therapeutic effect of APR-246 on TP53 mutant breast cancer in xenograft tumors. Our results suggested that intervention of PDK1 could potentially emerge as a new therapeutic strategy to impede the progression of TP53 mutant breast cancer.

The p53 reactivator APR-246 restores sensitivity of p53R273H-expressing cells to LT1-3. Therefore, LT1-3 possesses multifunctional antitumor properties, directly inhibiting tumor cells and enhancing the efficacy of cisplatin, without causing toxicity to normal cells. Combining LT1-3 with cisplatin holds promise as a first-line therapy for lung cancer, while LT1-3 alone may be suitable for maintenance therapy.

IQCE emerges as a novel oncogene-associated biomarker with significant diagnostic and prognostic utility, particularly in SKCM. It promotes an immunosuppressive TME and oncogenic signaling while being localized to malignant cells. Although associated with chemoresistance, the vulnerability of IQCE-high tumors to RITA offers a promising therapeutic strategy. IQCE represents a compelling target for precision oncology.

In this work, we show that missense mutant forms of p53, which occur in >60% of HGSOC, bind and inhibit ERα function and confer resistance to fulvestrant and elacestrant. Mechanistically, we show that mutant p53 predominantly inhibits one arm of the ERα pathway-the transactivation of jointly regulated ERα-SP1 target genes such as the mTOR regulator DEPTOR We show that silencing mutant p53 restores the ability of ERα to transactivate ERα-SP1 target genes and renders HGSOC markedly more sensitive to endocrine therapy. Consistent with this premise, we show that the p53 mutant Y220C refolding compound rezatapopt enhances fulvestrant response in a Y220C mutant cell line.

P1/2, N=300, Recruiting, PMV Pharmaceuticals, Inc | N=230 --> 300 | Trial completion date: Jul 2026 --> Dec 2027 | Trial primary completion date: Mar 2026 --> Aug 2026

Furthermore, upon exposure to the combination of 10 μM Prima-1MET and 10 μM Tam, synergistic effects were detected, reflected by decreased viability, migration, altered morphology, and induction of apoptosis, along with downregulation of CCND1. Hence, these results emphasize the attractiveness of the combination of Prima-1MET and Tam as a therapeutic approach for TNBC and ER+ breast cancer, irrespective of p53 mutational status; therefore, these results encourage further preclinical and clinical studies, considering that the effective dose of Prima-1MET is less than the reported clinically achievable plasma level (∼80 μg/ml).

NCT04585750 (ClinicalTrials.gov).