bims-p53act 2026-05-03 papers

Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2531747123

DARPins as pan-reactivators of temperature-sensitive p53 cancer mutants.

Philipp Münick, Dimitrios-Ilias Balourdas, Julianne S Funk, Büşra Yüksel, Danai Mavridi, Justin Heftel, Birgit Dreier, Jonas V Schaefer, Birgit Schäfer, Stefan Knapp, Tümay Telatar, Baki Akgül, Andreas Plückthun, Thorsten Stiewe, Andreas C Joerger, Volker Dötsch.

The tumor suppressor p53 is the most frequently mutated protein in tumors and a target for drug development. More than 2000 cancer-associated p53 missense mutations have been reported, most of them located in the DNA-binding domain (DBD). Due to the low intrinsic thermostability of the latter, they often lead to unfolding at physiological temperature. Stabilizing the DBD with small molecules has been shown to be effective in reactivating the cavity-creating cancer mutant Y220C. Unfortunately, the majority of p53 mutants seem to lack druggable binding pockets for small molecules. Here we show that a designed ankyrin repeat protein (DARPin) that binds to the p53 DBD stabilizes temperature-sensitive (TS) p53 cancer mutants, thereby compensating for mutation-induced loss of stability. We determined high-resolution crystal structures of multiple DARPin-mutant p53 complexes, providing mechanistic insights into this mode of stabilization. Reporter gene assays across a comprehensive panel of cancer-associated mutants revealed reactivation of the majority of TS mutants, whereas DNA-contact mutants and those with local misfolding of the DNA-binding surface remained inactive, as expected. We demonstrate that this reactivation induces the transcription of canonical p53 target genes and elicits antiproliferative effects in cancer cell lines. A combination of this DARPin with an mRNA/lipid nanoparticle-based transfection approach may have the potential to reactivate most TS p53 mutants and resensitize cancer cells to chemotherapy.

Keywords: DARPin; cancer; mutation; p53; reactivation

DOI: https://doi.org/10.1073/pnas.2531747123

Ann Hematol. 2026 May 02. pii: 280. [Epub ahead of print]105(5):

Serositis as possible manifestation in MDS/AML patients with complex karyotype and TP53 mutation: case series.

Eleonora Gugole, Edoardo Tamellini, Sara Jance, Nicola Serafin, Pietro Antonini, Chiara Colato, Mauro Krampera, Isacco Ferrarini, Ilaria Tanasi.

Myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML) are increasingly recognized to exhibit immune dysregulation, which can occasionally present with autoinflammatory manifestations. We describe four patients with MDS/AML harboring p53 mutations and a complex karyotype who developed inflammatory serositis without infectious correlation. All patients showed clinical improvement following corticosteroid therapy.

Keywords: Complex karyotype; MDS/AML; Serositis; Steroid therapy; TP53 mutation

DOI: https://doi.org/10.1007/s00277-026-06960-y

Nat Commun. 2026 May 02.

Activating p53Y220C with a mutant-specific small molecule.

Xijun Zhu, Woong Sub Byun, Dominika Ewa Pieńkowska, Kha The Nguyen, Mengxiong Wang, Sabin A Nettles, Sai Gourisankar, Nick A Phillips, Jan Gerhartz, Qixiang Geng, Tian Qiu, Jianing Zhong, Zixuan Jiang, Roman C Sarott, Stephen M Hinshaw, Tinghu Zhang, Laura D Attardi, Radosław P Nowak, Nathanael S Gray.

TP53 is the most commonly mutated gene in cancer, but it remains recalcitrant to clinically meaningful therapeutic reactivation. We present here the discovery and characterization of a small molecule chemical inducer of proximity that activates mutant p53. We named this compound TRanscriptional Activator of p53 (TRAP-1) due to its ability to engage p53Y220C and BRD4 in a ternary complex, which potently activates mutant p53 and triggers robust p53 target gene transcription. Treatment of p53Y220C-expressing cell lines with TRAP-1 results in rapid upregulation of CDKN1A and other p53 target genes and induces cellular senescence and apoptosis. Negative control compounds that are unable to form a ternary complex lack these activities, demonstrating the necessity of chemically induced proximity for the observed pharmacology. This approach to activating mutant p53 highlights how chemically induced proximity can be used to restore the functions of tumor suppressor proteins that have been inactivated by mutation in cancer.

DOI: https://doi.org/10.1038/s41467-026-72165-6

Curr Oncol. 2026 Apr 15. pii: 216. [Epub ahead of print]33(4):

Molecular Profiling and Survival Outcomes in Pancreatic Ductal Adenocarcinoma: A Multicenter Real-World Study from Turkey.

Selami Bayram, Bahadır Köylü, Maral Martin Mıldanoğlu, Mustafa Serkan Alemdar, Tahir Yerlikaya, Fatih Selçukbiricik, Ahmet Bilici, Ali Murat Tatli, Mustafa Ozdogan.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy. Next-generation sequencing (NGS) enables molecular characterization and may identify clinically actionable alterations; however, real-world multicenter data linking genomic subgroups to survival outcomes remain limited. We aimed to characterize the molecular landscape of NGS-tested PDAC in a Turkish multicenter cohort and evaluate the association of key molecular alterations, including KRAS status and KRAS variant subgroups, with survival outcomes. Methods: We conducted a multicenter retrospective cohort study including patients with pathologically diagnosed PDAC between 2017 and 2025 who underwent tumor-based NGS in routine clinical practice. Overall survival (OS) was calculated from the date of metastasis, defined as the date of diagnosis for de novo metastatic disease and the date of first documented distant recurrence for recurrent cases. Progression-free survival (PFS) was calculated from the initiation of first-line systemic therapy for metastatic disease to progression or death. Survival was estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariable Cox proportional hazards models were constructed for OS and PFS using clinically relevant covariates selected a priori. Results: A total of 98 patients underwent molecular profiling, and survival analyses were performed in 92 patients with available OS/PFS data. KRAS mutations were detected in 83.7% (82/98) of patients, with predominant variants G12D (47.6%), G12V (30.5%), and G12R (12.2%). TP53 mutations were present in 59.2% (58/98) of tumors, and all tumors were microsatellite stable. Tumor mutational burden data were available for 72 patients; the median TMB was 3.83 mutations/Mb, and 15.3% of evaluable tumors had a TMB ≥ 10 mutations/Mb. Excluding KRAS, clinically actionable alterations were identified in 4.1% of patients, whereas an additional 32.7% harbored potentially actionable or investigational alterations. Median OS was 14.0 months (95% CI, 11.7-16.3), and median PFS was 6.0 months (95% CI, 4.3-7.7). In unadjusted analyses, OS and PFS did not differ significantly according to KRAS mutation status (OS, p = 0.967; PFS, p = 0.652), TP53 mutation status (OS, p = 0.404; PFS, p = 0.510), or KRAS variant subgroup (OS, p = 0.332; PFS, p = 0.194). In multivariable Cox analyses, KRAS mutation status was not independently associated with OS (aHR 1.13, 95% CI 0.56-2.28; p = 0.727) or PFS (aHR 1.09, 95% CI 0.59-2.01; p = 0.780), whereas ECOG performance status remained the strongest adverse clinical factor. Conclusions: In this multicenter real-world PDAC cohort, the molecular landscape was dominated by KRAS and TP53 alterations, whereas clinically actionable non-KRAS alterations were identified in only a minority of patients. After adjustment for major clinical covariates, KRAS mutation status was not independently associated with OS or PFS. Molecular profiling may still be useful for identifying uncommon potentially targetable alterations; however, larger clinically annotated multicenter studies are needed to better define its prognostic and treatment-directing value in routine practice.

Keywords: KRAS; TP53; molecular profiling; next-generation sequencing; overall survival; pancreatic ductal adenocarcinoma; precision oncology; progression-free survival; real-world study; tumor mutational burden

DOI: https://doi.org/10.3390/curroncol33040216

J Clin Oncol. 2026 Apr 29. JCO2501928

Integrative Molecular Analysis Reveals Determinants of Clinical Outcomes in TP53-Mutated Diffuse Large B-Cell Lymphoma.

PURPOSE: Mutations in TP53, detected in over 20% of diffuse large B-cell lymphomas (DLBCLs), are associated with poor prognosis. However, clinical outcomes among patients with TP53-mutant disease vary, with some patients showing treatment responses similar to those with wild-type TP53. This study aims to understand the clinical and molecular determinants underlying poor outcomes in TP53-mutant DLBCL.
METHODS: Clinical and molecular data for 3,091 patients were derived from 10 cohorts of patients with newly diagnosed DLBCL treated with frontline rituximab-based immunochemotherapy regimens. Targeted or whole-exome/whole-genome sequencing was available for all patients. Bulk RNA-seq was analyzed for 591 patient samples. The primary outcome measures were progression-free survival (PFS) and overall survival (OS).
RESULTS: TP53-mutant DLBCL differed from wild-type disease in pattern and number of genetic lesions, malignant B-cell expression states, and tumor microenvironment composition. TP53 mutations were 6-fold more prevalent than MYC/BCL2/BCL6 double-/triple-hit status, but conferred similar adverse prognostic risk. Among patients with TP53-mutant disease, variant allele frequency (VAF) further stratified risk, with patients featuring VAF ≥ 75% (indicative of loss of heterozygosity) experiencing significantly inferior PFS/OS. Downregulation of interferon signaling and lower macrophage content were identified in TP53-mutant samples derived from patients with poor outcomes or VAF ≥ 75%. TP53 mutations were adversely prognostic among patients with DLBCL assigned to specific LymphGen subtypes (EZB, MCD), malignant B-cell states (S1), and ecotypes (LE4, LE7, LE8), whereas outcomes were similar to wild-type disease within other molecular subtypes. In re-examination of the Phoenix trial data, addition of ibrutinib to R-CHOP improved PFS in patients with TP53-mutant DLBCL and abrogated the deleterious impact of high VAF, irrespective of patients' age.
CONCLUSION: The poor prognosis of TP53-mutant DLBCL is dependent on intrinsic features, such as VAF, and modulated by co-occurring genomic lesions or lymphoma cell-intrinsic or microenvironmental expression patterns.

DOI: https://doi.org/10.1200/JCO-25-01928