2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T442,The tumor suppressor TP53 is the most frequently altered gene in cancer, and the Y220C hotspot, found in 1.8% of TP53-mutant tumors, creates a druggable cavity that destabilizes p53. Rezatapopt, a first-in-class, orally bioavailable reactivator of Y220C-mutant p53, has demonstrated promising initial efficacy in the phase 1/2 PYNNACLE trial. We report the first clinical mechanisms of resistance to this therapeutic class. Profiling of circulating tumor DNA, tumor biopsies, and rapid autopsy specimens upon rezatapopt progression revealed multiple heterogenous secondary TP53 alterations in cis with Y220C, including: (1) DNA-binding domain mutations or frameshift/nonsense mutations that abolish transcriptional activity, and (2) mutations within the Y220C binding surface predicted to hinder drug binding. 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.31:T487,Abstract The tumor suppressor TP53 is the most frequently altered gene in cancer, and the Y220C hotspot, found in 1.8% of TP53-mutant tumors, creates a druggable cavity that destabilizes p53. Rezatapopt, a first-in-class, orally bioavailable reactivator of Y220C-mutant p53, has demonstrated promising initial efficacy in the phase 1/2 PYNNACLE trial. We report the first clinical mechanisms of resistance to this therapeutic class. Profiling of circulating tumor DNA, tumor biopsies, and rapid autopsy specimens upon rezatapopt progression revealed multiple heterogenous secondary TP53 alterations in cis with Y220C, including: (1) DNA-binding domain mutations or frameshift/nonsense mutations that abolish transcriptional activity, and (2) mutations within the Y220C binding surface predicted to hinder drug binding. 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.32:T4cf,TP53-mutated (TP53-MT) myeloid neoplasms (MN) represent one of the most challenging disease subsets due to their distinct pathobiology, frequent association with therapy-related disease, chemo-resistant phenotype, and dismal outcomes. The prognostic impact of TP53-MT is not uniform and is influenced by disease state, allelic burden, and co-occurring cytogenetic and molecular aberrations that shape disease trajectory. While current prognostic models incorporate TP53 status, they incompletely capture the heterogeneity within TP53-MT MN. Therapeutic options remain limited, with allogeneic stem cell transplantation being the only intervention offering long-term survival in selected patients. Novel approaches, including p53 reactivators and anti-CD47 antibodies in combination with standard-of-care therapies, have been explored; however, none has yet transformed the natural history of TP53-MT MN. This review highlights the current understanding of TP53-MT MN, evolving strategies of prognostic stratification and propose a practical framework for clinical management. We further discuss the critical unmet need for collaborative, biologically informed clinical trials to improve outcomes of this challenging disease entity.33:T94f, Purpose of review TP53- mutated ( TP53 -MT) myeloid neoplasms (MN) represent one of the most challenging disease subsets due to their distinct pathobiology, frequent association with therapy-related disease, chemo-resistant phenotype, and dismal outcomes. The prognostic impact of TP53 -MT is not uniform and is influenced by disease state, allelic burden, and co-occurring cytogenetic and molecular aberrations that shape disease trajectory. While current prognostic models incorporate TP53 status, they incompletely capture the heterogeneity within TP53 -MT MN. Therapeutic options remain limited, with allogeneic stem cell transplantation being the only intervention offering long-term survival in selected patients. Recent findings Novel approaches, including p53 reactivators and anti-CD47 antibodies in combination with standard-of-care therapies, have been explored; however, none has yet transformed the natural history of TP53 -MT MN. Summary This review highlights the current understanding of TP53 -MT MN, evolving strategies of prognostic stratification and propose a practical framework for clinical management. We further discuss the critical unmet need for collaborative, biologically informed clinical trials to improve outcomes of this challenging disease entity. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"p53 Reactivator: modality Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on p53 Reactivator (modality). Clinician-written summaries and actionable practice insights. 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The study integrates clinical specimens with laboratory modeling, and detailed methods and outcomes are not provided in the abstract.","practice_takeaway":"In patients progressing on rezatapopt, acquired on‑target TP53 alterations in cis with Y220C can drive resistance; profiling ctDNA or tumor tissue at progression may reveal these changes and explain loss of response."}},{"doi":"10.1097/moh.0000000000000906","pmid":"41496439","title":"Navigating prognostic stratification and approach to TP53-mutated myeloid neoplasms","journal_title":"Current Opinion in Hematology","journal_issn":"1065-6251","published_at":"2026-01-07T00:00:00.000Z","url":"https://doi.org/10.1097/moh.0000000000000906","source_score":11,"is_retracted":false,"is_open_access":null,"raw_metadata":{"ooir":{"day":"2026-01-08","doi":"10.1097/moh.0000000000000906","days":"7","issn":"1065-6251","rank":"10","field":"Clinical 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anti‑CD47 antibodies with standard care) have not yet changed the natural history.","limitations":"Narrative review without quantitative outcomes in the abstract; no sample sizes or effect estimates are provided; prognostic models are noted to incompletely capture heterogeneity within TP53‑mutated disease.","practice_takeaway":"Refer eligible patients for allogeneic transplantation when feasible. 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