TP53 wild-type

Using B-ALL cell lines and patient-derived xenografts, we show that FATP2-expressing TP53-mutant B-ALL resistance to CAR-T is dependent on exogenous lipid uptake to fuel fatty acid oxidation (FAO) and cell survival, which can be pharmacologically targeted through inhibition of neutral lipolysis and CPT1. These findings identify FATP2-mediated fatty acid uptake and downstream FAO as a potential target to improve existing CAR-T efficacy in human B-ALL.

We demonstrate that MDM2 degraders KTX-049 and KT-253 overcome this limitation by collapsing the p53/MDM2 negative feedback loop. KTX-049 was >100-fold more potent than the MDM2 inhibitor DS-3032 across WT p53 MCC cell lines, and this superior potency was quantitatively supported by mechanistic mathematical modeling...Acquired resistance was strongly associated with acquisition of TP53 mutations, confirming on-target pathway pressure. These findings establish feedback architecture as a critical determinant of therapeutic response and position MDM2 degradation as a qualitatively distinct strategy that produces more durable pathway engagement than MDM2 inhibition, providing a preclinical rationale for prioritizing MDM2 degraders in WT TP53 MCC.

Clinically, elevated LFPM expression correlates with poorer survival, specifically in p53R175H-mutant cancers. Our work unveils a pivotal mechanism for mutant p53 stabilization and nominates the LFPM-p53R175H axis as a promising therapeutic target.

In Huh7 cells, it suppressed TAp63/Bax-mediated apoptosis while driving both oxidative phosphorylation and glycolysis, promoting resistance despite the absence of wild-type p53. These findings identify miR-203a-3p as a key modulator of DOX resistance in HCC through coordinated regulation of p53 family expression, apoptotic signaling, and metabolic rewiring, highlighting its potential as a therapeutic target for miRNA-based combination therapies.

Recently, the randomized phase III VERONA study evaluating azacitidine plus venetoclax (VEN) versus azacitidine plus placebo in newly diagnosed HR-MDS showed no difference in overall survival (OS) between the two arms. However, we did not observe a statistically significant difference in OS for HMA/VEN vs. HMA monotherapy (Hazard Ratio [HR]: 0.83; 95% CI: 0.64-1.07; p = 0.15). In subgroup analyses, patients with TP53 wild-type disease (HR: 0.47; 95% CI: 0.29-0.74; p = 0.002) had a significant improvement in OS and those with ≥10% bone marrow blasts (HR: 0.73; 95% CI: 0.53-1.01; p = 0.06) had a trend towards OS benefit with HMA/VEN.

These findings suggest that molecular stratification could support risk assessment and therapeutic decision-making in UCS. Larger prospective multicenter studies are warranted to validate these findings and clarify their potential clinical implications.

Summary and Outlook: An understanding of the crosstalk of these molecular pathways will be critical in designing rational therapeutic strategies. Genetics, metabolism, and microenvironmental integration may open a path toward combinatorial therapies that would resensitize PDAC to apoptosis and overcome resistance to current treatments.

5d induces a cellular phenotype consistent with replication stress, including reduced EdU incorporation, γH2AX accumulation, cell cycle arrest, and apoptotic cell death in a p53 status-dependent manner. These findings establish benzofuran-annulated naphthalimides as a promising scaffold for the development of anticancer agents that exploit replication stress vulnerabilities in tumor cells.

DCAF13 is overexpressed in PDAC and associated with poor prognosis. DCAF13 may promote malignant phenotypes in vitro and alter p53-related signaling in TP53-mutant PDAC cells. These findings suggest that DCAF13 may have potential value as a prognostic biomarker and exploratory therapeutic candidate for PDAC, although further validation in WT-p53 and in vivo models is still required.

The mOS of the EGFR-TP53 co-mutant group who received second-line TKIs combined with platinum-containing double-drug chemotherapy and bevacizumab after the progression of first-line single-drug TKIs was 27.0 months versus 6.0 months compared with those who did not receive second-line therapy (P = .019). In first-line EGFR-TKIs monotherapy in patients with EGFR-TP53 co-mutation, osimertinib was clearly superior to gefitinib. In first-line EGFR-TKIs monotherapy progression, TKIs combined with chemotherapy and antiangiogenesis therapy could prolong patients' survival.

Rescue experiments and xenograft studies further verified this regulatory axis. KDM4D enhances ESCC radiosensitivity through the SRBD1/RPL11/c-Myc/WIP1/CHK1 pathway, highlighting its potential as both a diagnostic biomarker and a therapeutic target.

In this review, we summarize the biological roles of p53, examine how TP53 gene alterations drive therapeutic resistance in myeloid neoplasms, and compare contemporary classification frameworks, including their limitations and proposed refinements. We also highlight standard and emerging therapeutic strategies aimed specifically at TP53-mutated myeloid neoplasms.