bims-p53act 2026-03-01 papers

bims-p53act

Biomed News

on p53 mutations and anti-cancer therapy response

Issue of 2026–03–01
thirteen papers selected by
Toni Martínez Bernabé, Universitat de les Illes Balears

Lung cancer-enriched p53 mutants occupy canonical p53 target genes without activating transcription, revealing a distinct loss-of-function behavior.
Effect of p53 gene mutation with loss of function on the expression of genes and proteins involved in cell proliferation.
The impact of p53 mutation on tumor immune evasion: mechanistic insights and clinical implications.
Strategic selection of MDM2 inhibitors enhances the efficacy of FAK inhibition in mesothelioma based on TP53 genotype.
Impact of TP53, KEAP1 and STK11 mutations in localized-stage NSCLC: A European thoracic oncology platform lungscape project.
TP53 Functional-Domain-Specific Mutations Define Distinct Clinical Outcomes in EGFR-Mutant Non-Small Cell Lung Cancer Treated with EGFR Tyrosine Kinase Inhibitors.
Risk stratification of patients with TP53-mutated myeloproliferative neoplasms.
Integrative Computational Analysis of TP53 Exon 5-6 Mutations in Oral Cavity, Prostate, and Breast Cancers in a Senegalese Population.
"Pioneering" p53 Reactivator Shows Proof-of-Concept in Phase I Trial.
Targeting the p53 cancer mutants Y220C, Y220N, and Y220S with the small-molecule stabilizer rezatapopt.
Phase 1 Study of Rezatapopt, a p53 Reactivator, in TP53 Y220C-Mutated Tumors.
Clonal Dynamics and Molecular Heterogeneity of Metaplastic Breast Cancer: Focus on TP53 and PIK3CA Truncal Mutations.
ROR1-PI3K/AKT signaling drives adaptive resistance to cell cycle blockade in TP53 mutated ovarian cancer.

bioRxiv. 2026 Feb 17. pii: 2026.02.14.705936. [Epub ahead of print]

Lung cancer-enriched p53 mutants occupy canonical p53 target genes without activating transcription, revealing a distinct loss-of-function behavior.

Mason A Tracewell, Hailey N Shankle, Samantha M Barnada, Khushali S Vyas, Kevin M Kim, Theodhora Qyshkollari, Jonathan E Karlin, Julie A Barta, Steven B McMahon.

Lung cancer is the most common cause of cancer-related death in the U.S. and globally. Cigarette smoking remains the leading risk factor for lung cancer, in part by inducing loss-of-function mutations in tumor suppressor genes, including TP53 . While most cancers share a set of common "hotspot" mutations in p53, lung cancer exhibits an additional, distinct cluster of hotspot mutations. This cluster is typified by the missense mutations TP53 :p.V157F and TP53 :p.R158L. While canonical hotspot mutations cause broad misfolding of p53 or eliminate specific DNA contact residues, mechanistic studies of the lung cancer mutants reported here demonstrate that they retain the ability to bind the same genomic sites as wild-type p53. Despite actively binding to traditional p53 target genes, the lung cancer mutants are defective in activating transcription. To our knowledge, this represents the first demonstration of functional inactivation of the p53 tumor suppressor at a point after DNA binding, but prior to target gene activation. Relevant to the sequential inactivation of each p53 allele during cancer progression, the lung cancer mutants block the activity of a wild-type p53 allele when co-expressed in a dominant negative manner. Identification of this loss-of-function mechanism has key implications for therapeutic strategies aimed at restoring p53 function in lung cancer.

DOI: https://doi.org/10.64898/2026.02.14.705936
Mutat Res. 2026 Feb 22. pii: S1386-1964(26)00004-7. [Epub ahead of print]832 111931

Effect of p53 gene mutation with loss of function on the expression of genes and proteins involved in cell proliferation.

Gyeong Hee Kim, Moon-Moo Kim.

  The tumor suppressor gene TP53 plays a vital role in preserving genomic integrity by regulating cell cycle progression, DNA repair mechanisms, and apoptosis. This study aims to examine how CRISPR/Cas9-induced loss-of-function mutations in the p53 gene influence cellular processes on cell cycle regulation and tumorigenic signaling in HT1080 human fibrosarcoma cells. Successful TP53 gene disruption was confirmed by Sanger sequencing, and its structural modelling using AlphaFold2 and ChimeraX confirmed alterations in the predicted TP53 protein structure compared to that of wild type. Gene expression analyses, conducted via RT-PCR and qPCR, demonstrated a marked decrease in TP53 mRNA expression within the modified cells. Despite the mutation, the edited cells elevated activity of the senescence marker β-galactosidase (SA-β-gal). They decreased the production of collagen, suggesting that the structural disruption caused by CRISPR/Cas9 leads to the loss of functional p53 activity. Western blotting and immunofluorescence assays further revealed a remarkable downregulation of key cell cycle and tumorigenesis-related proteins, including TP53, phosphorylated TP53 (p-TP53), acetylated TP53 (ac-TP53), MMP-2, cyclin D, cyclin E, AKT, BAX, MDM2, and phosphorylated Rb (p-Rb) in the edited cells relative to the wild-type counterpart. Our results suggest that the TP53 mutation may disrupt essential pathways related to cell proliferation and stress responses. This provides new insights into TP53 functionality and underscores its potential as a therapeutic target in cancer biology.

Keywords:  CRISPR/Cas9 system; Cell cycle; Cell proliferation; HT1080; P21; P53

DOI:  https://doi.org/10.1016/j.mrfmmm.2026.111931
Front Immunol. 2026 ;17 1753215

The impact of p53 mutation on tumor immune evasion: mechanistic insights and clinical implications.

Luo Liang, Weidong Wang.

  Mutant p53(Mtp53) not only loses its canonical tumor-suppressive functions but also acquires oncogenic gain-of-function properties, positioning it as a central orchestrator in reshaping the tumor immune microenvironment. This review systematically delineates how Mtp53 actively establishes and sustains an immunosuppressive niche through multiple interconnected mechanisms, including chronic inflammation, immune cell dysfunction, reprogramming of cancer-associated fibroblasts, metabolic dysregulation, epigenetic hijacking, and potentially aberrant liquid-liquid phase separation, thereby promoting immune evasion and therapeutic resistance. We integrate current evidence to propose a conceptual "metabolism-epigenetics-immunity" axis: Mtp53-driven metabolic reprogramming-such as accumulation of lactate or α-ketoglutarate-can modulate chromatin modifications and immune gene expression. Notably, the full in vivo causal chain of this axis remains unestablished; existing support derives primarily from stepwise experimental data and strong correlations. The immunological impact of Mtp53 is highly context-dependent, shaped by co-mutations and tissue origin. In TP53/KRAS co-mutant non-small cell lung cancer (NSCLC), Mtp53 enhances tumor immunogenicity and improves response to immune checkpoint inhibitors (ICIs); conversely, in immunologically "cold" tumors-such as triple-negative breast cancer, pancreatic ductal adenocarcinoma, and colorectal cancer-it promotes T-cell exhaustion or myeloid suppression, reflecting marked cancer-type heterogeneity. Therapeutic approaches include Mtp53 reactivators (e.g., APR-246, PC14586), degraders, synthetic lethal strategies, and neoantigen vaccines. Although APR-246 showed efficacy in a phase II trial (NCT03072043), it failed to improve survival in phase III (NCT03745716) due to lack of TP53 mutation stratification. Its combination with pembrolizumab (NCT04383938) demonstrated acceptable safety (immune-related adverse events in ∼12%) but limited efficacy, underscoring the need for biomarker-guided, precision-based combinations. Thus, a multidimensional biomarker platform is urgently needed-one integrating TP53 mutation subtypes (e.g., R175H vs. nonsense mutations), dynamic ctDNA monitoring (VAF ≥ 0.01%), tumor immune microenvironment (TIME) features (e.g., TILs, MDSCs), and spatial multi-omics-to enable precise molecular stratification and personalized intervention in Mtp53-driven cancers.

Keywords:  epigenetic regulation; immune evasion; immunotherapy; metabolic reprogramming; p53 mutation; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1753215
PLoS One. 2026 ;21(2): e0343551

Strategic selection of MDM2 inhibitors enhances the efficacy of FAK inhibition in mesothelioma based on TP53 genotype.

Xuerao Ning, Thảo Thi Thanh Nguyễn, Takao Morinaga, Yuji Tada, Hideaki Shimada, Kenzo Hiroshima, Naoto Yamaguchi, Masatoshi Tagawa.

Mesothelioma has characteristic genetic changes including inactivation of neurofibromatosis type 2 (NF2) and deletion of the INK4A/ARF region. Cells deficient of NF2 protein (MERLIN) depend on focal adhesion kinase (FAK) for cell adhesion and FAK inhibitors suppress the cell growth. The INK4A/ARF deletion activates MDM2 functions which ubiquitinate and degrade p53, and consequently the cellular p53 levels decrease. The deletion therefore induces loss of p53 functions although a majority of mesothelioma has wild-type TP53 genotype. An MDM2 inhibitor which blocked the ubiquitination increased p53 levels, restored p53 functions and facilitated cell growth arrest. Moreover, FAK and p53 expressions were reciprocally regulated. We examined growth suppressive effects of a FAK inhibitor, defactinib, and MDM2 inhibitors, nutlin-3a and reactivation of p53 and induction of tumor cell apoptosis (RITA), with representative wild-type and mutated TP53 mesothelioma and investigated molecular changes induced by the agents. We analyzed possible combinatory effects of the inhibitors and molecular changes caused by the combination. Our study showed that defactinib inhibited cell growth and induced FAK dephosphorylation irrespective of the TP53 genotype, and that the inhibited FAK phosphorylation was not associated with MERLIN levels or with p53 up-regulation, but linked with AKT dephosphorylation. Nutlin-3a preferentially suppressed growth of wild-type TP53 cells and augment p53 expression without DNA damage, whereas RITA-mediated p53 up-regulation was linked with the damage. 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.

DOI: https://doi.org/10.1371/journal.pone.0343551
Eur J Cancer. 2026 Feb 17. pii: S0959-8049(26)00363-1. [Epub ahead of print] 116583

Impact of TP53, KEAP1 and STK11 mutations in localized-stage NSCLC: A European thoracic oncology platform lungscape project.

Miguel A Molina-Vila, Zoi Tsourti, Katerina Vervita, Jordi Bertran-Alamillo, Beatriz García-Peláez, Keith M Kerr, Lukas Bubendorf, Line Bille Madsen, Wojciech Biernat, Albrecht Stenzinger, Martina Haberecker, Fiona Blackhall, Saraswati Pokharel, Núria Jordana-Ariza, Marta Vives-Usano, Patrick Vagenknecht, Urania Dafni, Roswitha Kammler, Stephen P Finn, Solange Peters, Rolf A Stahel, Rafael Rosell.

   BACKGROUND: TP53, STK11 and KEAP1 mutations are frequent in localized-stage non-small cell lung cancer (NSCLC). However, their prognostic and predictive role has not been fully investigated, particularly in relation to adjuvant treatment.
METHODS: Tumor samples from a training cohort of 350 surgically resected ETOP Lungscape NSCLC patients and a validation cohort of 161 additional patients were genotyped using Next Generation Sequencing (NGS). TP53 mutations were classified as "disruptive" (d) or "non-disruptive" (nd) according to their predicted impact. Disruptive mutations are those leading to complete loss of function of the p53 protein.
RESULTS: Among the 350 patients of the training cohort, 11 % harbored mutations in KEAP1 and 14 % in STK11. Regarding TP53 status, 31 % were wild type, 35 % carried TP53-d and 34 % TP53-nd mutations. For the 161 patients receiving adjuvant chemotherapy, TP53-d mutations associated with better time to relapse (TTR). Significantly shorter TTR and overall survival (OS) were observed in KEAP1 mutant patients while STK11 mutations correlated with better outcomes. Among the 186 patients not receiving chemotherapy, significantly worse OS was observed in KEAP1 mutant patients, while TP53 or STK11 status did not affect outcome. In a baseline-matched sub-cohort (n = 206), selected within the training cohort, the interaction between TP53 mutations and chemotherapy was statistically significant for all endpoints. The findings for KEAP1 but not for TP53 were validated in a second cohort of 161 patients.
CONCLUSIONS: TP53-d and STK11 mutations might have a predictive impact in localized-stage NSCLC, but further investigation is needed. KEAP1 mutations associate with worse outcomes, especially in patients receiving adjuvant chemotherapy.

Keywords:  KEAP1; Localized; Mutations; NSCLC; Predictive; Prognostic; STK11; TP53

DOI:  https://doi.org/10.1016/j.ejca.2026.116583
J Clin Med. 2026 Feb 15. pii: 1552. [Epub ahead of print]15(4):

TP53 Functional-Domain-Specific Mutations Define Distinct Clinical Outcomes in EGFR-Mutant Non-Small Cell Lung Cancer Treated with EGFR Tyrosine Kinase Inhibitors.

Keigo Kobayashi.

  Background: In advanced non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations, EGFR tyrosine kinase inhibitors (EGFR-TKIs) improve progression-free survival (PFS). However, clinical outcomes vary according to EGFR mutation subtype and TP53 co-mutations. Most prior studies have evaluated TP53 status as binary, and the clinical relevance of domain-specific TP53 alterations remains insufficiently defined. Methods: We retrospectively analyzed patients with advanced NSCLC harboring sensitizing EGFR mutations who received first-line EGFR-TKI therapy at the National Cancer Centre Singapore between 22 November 2007, and 17 February 2022. EGFR mutations were classified as common (exon 19 deletion or L858R) or uncommon (all others). TP53 alterations were categorized into three groups: (i) DNA-binding domain (DBD)-involved mutations, including DBD-only mutations and those with additional oligomerization domain (OD) involvement; (ii) other TP53 mutations not involving the DBD or OD; and (iii) TP53 wild type (TP53-WT). The primary endpoint was PFS. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards models. Results: TP53 alterations were identified in approximately half of the cohort and were predominantly concentrated within the DBD. In the overall cohort, patients treated with third-generation EGFR-TKIs had longer PFS than those treated with first- or second-generation EGFR-TKIs, with this difference being more pronounced among patients with TP53-mutant tumors; no clear PFS difference by TKI generation was observed in the TP53-WT subgroup. Patients with common EGFR mutations experienced significantly longer PFS than those with uncommon mutations, particularly in the presence of TP53 co-mutations. Across multiple analyses, TP53 DBD-involved mutations were associated with shorter PFS compared with other TP53 mutations and TP53-WT, especially in patients treated with first- or second-generation EGFR-TKIs and in those with common EGFR mutations. Conclusions: In EGFR-mutant NSCLC treated with EGFR-TKIs, TP53 functional domain involvement provides prognostic information beyond TP53 mutation status alone. TP53 DBD-involved alterations define a high-risk subgroup with inferior PFS, particularly in treatment settings using first- or second-generation EGFR-TKIs. Incorporation of TP53 domain-based classification, together with EGFR mutation subtype, may improve risk stratification and help guide treatment planning in EGFR-mutant NSCLC.

Keywords:  DNA-binding domain; EGFR tyrosine kinase inhibitors; EGFR-mutant non-small cell lung cancer; TP53 functional domain mutation; clinical decision making; prognostic stratification

DOI:  https://doi.org/10.3390/jcm15041552
Leukemia. 2026 Feb 24.

Risk stratification of patients with TP53-mutated myeloproliferative neoplasms.

Benjamin Rolles, Cilomar Martins de Oliveira Filho, Nathan Fergusson, Jan Philipp Bewersdorf, Julia Keating, Cecelia Perkins, Matthew Schwede, James England, Marlise R Luskin, Daniel J DeAngelo, Shai Shimony, Mifra Faiz, Addison C Hillerbrand, Chulwoo Kim, Lachelle D Weeks, Lauren Waldman, Mohammed Wazir, Joan How, Anna E Marneth, Yiwen Liu, Martin J Aryee, Raajit Rampal, Harrison K Tsai, Jason Gotlib, Vikas Gupta, Maximilian Stahl, Ann Mullally.

While TP53 mutations in myeloproliferative neoplasms (MPN) are associated with an increased risk of leukemic transformation, not all patients carrying a TP53 mutation progress. To better risk-stratify MPN patients with TP53 mutations, we analyzed data from 1540 patients treated at four specialized cancer centers. Among them, 1429 had wildtype TP53 and 111 had mutations in the TP53 gene. At first MPN diagnosis, 32% had polycythemia vera, 39% had essential thrombocythemia, and 25% had primary myelofibrosis. Among all MPN patients with TP53 mutations, presence of fibrosis in the bone marrow (hazard ratio (HR): 3.84, 95% CI: 1.98-7.43), multi-hit TP53 mutation status (HR: 2.74, 95% confidence interval (CI): 1.52-4.97), and higher PHANTM score (HR: 1.87, 95% CI: 1.02-3.42) were associated with worse OS in a multivariable analysis. Based on these variables, we developed a risk model to identify TP53-mutated MPN patients who are at high risk for inferior OS. Median OS from time of TP53 detection was 0.5 years in high-risk patients, compared to 2.3 years for patients with intermediate risk and 6.3 years for patients with low risk. This scoring system may help refine risk stratification for chronic phase MPN patients harboring TP53 aberrations.

DOI: https://doi.org/10.1038/s41375-026-02885-7
Genes (Basel). 2026 Feb 20. pii: 245. [Epub ahead of print]17(2):

Integrative Computational Analysis of TP53 Exon 5-6 Mutations in Oral Cavity, Prostate, and Breast Cancers in a Senegalese Population.

Mouhamed Mbaye, Fatimata Mbaye, Mbacke Sembene.

  Background/Objectives: The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancers, with alterations predominantly affecting its DNA-binding domain (DBD). However, the mutational landscape and functional consequences of TP53 variants remain poorly characterized in African populations. This study aimed to characterize mutations in exons 5-6 of TP53 in oral cavity cancer (OCC), prostate cancer (PC), and breast cancer (BC) in a Senegalese population, and to assess their structural effects, functional consequences, and impact on protein-protein interactions with BCL-2. Methods: Seventy-eight archived tumor DNA samples from Senegalese patients with OCC, PC, and BC were analyzed. Variants were annotated using COSMIC and dbSNP databases. Functional impact was evaluated with PolyPhen-2. Structural stability changes (ΔΔG) were predicted using FoldX, conformational dynamics (ΔΔSvib) were assessed with ENCoM, and effects on the p53-BCL-2 interaction were analyzed using DDMut-PPI. Statistical analyses were also performed. Results: BC exhibited the highest TP53 mutation frequency, whereas OCC showed greater mutational diversity. Exon-level analysis revealed a significant enrichment of exon 6 mutations in BC. Structural analyses indicated that exon 5 mutations across all cancers and mutations in OCC were predominantly destabilizing and associated with loss-of-function effects. In contrast, recurrent exon 6 mutations in PC and BC, particularly V217L and V218M, were predicted to stabilize the p53 structure. Conformational dynamics differences between exons were significant only in PC. All analyzed mutations were predicted to stabilize the p53-BCL-2 interaction. Conclusions: This integrative in silico study identified cancer and exon-specific TP53 mutation patterns in a Senegalese population, highlighting exon 6 as a context-dependent hotspot with potential oncogenic implication in PC and BC. Despite its computational nature, the study provides valuable insights that merit further investigation.

Keywords:  Senegal; TP53; bioinformatics; breast; cancer; mutation; oral cavity; prostate

DOI:  https://doi.org/10.3390/genes17020245
Cancer Discov. 2026 Feb 27. OF1

"Pioneering" p53 Reactivator Shows Proof-of-Concept in Phase I Trial.

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.

DOI: https://doi.org/10.1158/2159-8290.CD-NW2026-0020
Cell Death Dis. 2026 Feb 26.

Targeting the p53 cancer mutants Y220C, Y220N, and Y220S with the small-molecule stabilizer rezatapopt.

Danai Mavridi, Julianne S Funk, Dimitrios-Ilias Balourdas, Andreas Krämer, Raysa Khan Tareque, Oleg Timofeev, John Spencer, Thorsten Stiewe, Andreas C Joerger.

The cavity-creating p53 cancer mutation Y220C, which accounts for an estimated 125,000 new cancer cases per year, serves as an excellent paradigm for the development of mutant p53 reactivators. Several molecules that reactivate this thermolabile cancer mutant by targeting the mutation-induced crevice have been developed, and one of them, rezatapopt, is currently in clinical trials. The less frequently occurring Y220N and Y220S mutations are even more destabilizing than Y220C but create a similar surface crevice, raising the question of whether cancer patients with these mutations might also benefit from rezatapopt treatment. Here, we show that rezatapopt also binds to the Y220N and Y220S mutants, with nanomolar affinity, resulting in a full recovery of wild-type-like stability for the latter. High-resolution crystal structures of all three mutants bound to rezatapopt revealed a conserved binding mode, highlighting key interactions, including multipolar interactions of a fluorine substituent at a chiral center with the protein backbone. Consistent with the biophysical and structural data, rezatapopt reactivated p53 signaling in both Y220C and Y220S mutant cells by restoring the folded conformation and transcriptional activity, leading to anti-proliferative effects and apoptosis, albeit requiring higher compound concentrations in Y220S cells. 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.

DOI: https://doi.org/10.1038/s41419-026-08492-9
N Engl J Med. 2026 Feb 26. 394(9): 872-883

Phase 1 Study of Rezatapopt, a p53 Reactivator, in TP53 Y220C-Mutated Tumors.

Ecaterina E Dumbrava, Geoffrey I Shapiro, Aparna R Parikh, Melissa L Johnson, Anthony W Tolcher, John A Thompson, Anthony B El-Khoueiry, Andrae L Vandross, Shivaani Kummar, Dale R Shepard, Kim LeDuke, Lisa Sheehan, Leila Alland, Arshad Haque, Deepika Jalota, Marc Fellous, Alison M Schram.

BACKGROUND: Rezatapopt is an investigational, first-in-class, oral, selective p53 reactivator that specifically binds to Y220C-mutated p53, which stabilizes p53 in its wild-type conformation and restores its functionality.
METHODS: In this phase 1, single-group, dose-escalation and dose-optimization study, we assigned heavily pretreated patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation to receive rezatapopt during continuous 21-day treatment cycles. The primary objectives were to determine the maximum tolerated dose and recommended phase 2 dose. Primary end points included dose-limiting toxic effects and adverse events. Secondary end points included preliminary efficacy and pharmacokinetic features.
RESULTS: A total of 77 patients received rezatapopt at one of eight escalating doses: 150 mg, 300 mg, 600 mg, 1150 mg, 1500 mg, 2000 mg, or 2500 mg once daily or 1500 mg twice daily. The maximum tolerated dose was 1500 mg twice daily. On the basis of safety, efficacy, and pharmacokinetic data, 2000 mg once daily with food was selected as the recommended phase 2 dose. During the treatment period, 76 patients (99%) had at least one adverse event and 29 (38%) had an adverse event of grade 1 or 2. The most common adverse events were nausea (in 58% of patients), vomiting (in 44%), an increased blood creatinine level (in 39%), fatigue (in 39%), and anemia (in 36%). Treatment-related adverse events occurred in 67 patients (87%) and those of grade 1 or 2 in 48 (62%); 2 patients (3%) discontinued rezatapopt because of a treatment-related adverse event. Most gastrointestinal adverse events resolved with the treatment of symptoms and were less frequent when rezatapopt was given with food. Anemia was the most common adverse event of grade 3 or higher during the treatment period, occurring in 16% of patients. The overall response (complete or partial response) was 20% among all patients and 30% among those who had a KRAS wild-type tumor and received a dose of at least 1150 mg once daily. Confirmed responses were seen across multiple tumor types, including ovarian and breast cancers. All patients with a response had a solid tumor that harbored TP53 Y220C and wild-type KRAS.
CONCLUSIONS: 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.).

DOI: https://doi.org/10.1056/NEJMoa2508820
Breast Cancer (Dove Med Press). 2026 ;18 558033

Clonal Dynamics and Molecular Heterogeneity of Metaplastic Breast Cancer: Focus on TP53 and PIK3CA Truncal Mutations.

Rupei Ye, Xinzhi Dai, Zihan Yang, Dandan Zhang, Zhimin Hu, Yehui Liao, Zhihui Yang.

   Background: Metaplastic breast carcinoma (MBC) is a rare and aggressive subtype of triple-negative breast cancer with distinct molecular features that remain incompletely characterized, hindering the development of effective therapies.
Methods: We integrated clinicopathological data with next-generation sequencing (NGS) of 437 cancer-related genes performed on 25 tumor samples (16 primary, 8 lymph node metastases, 1 distant metastasis) from 17 MBC patients. Functional enrichment analysis was conducted to identify key signaling pathways.
Results: Recurrent alterations were identified in TP53 (14/16, 87.5%), PIK3CA (9/16, 56.2%), and MCL1 (10/16, 62.5% amplified). TP53 mutations (primarily frameshift and missense) showed consistent variant types between primary and metastatic sites. PIK3CA hotspot mutations (eg, H1047R, E545K) persisted across metastases. In contrast, MCL1 amplification exhibited dynamic evolution, being lost in some primary tumors but acquired de novo in lymph node metastases. Functional enrichment analysis revealed the PI3K-Akt signaling pathway as the most significantly altered pathway in MBC.
Conclusion: This study delineates the distinct mutational landscape and clonal evolution patterns of MBC, underpinned by truncal mutations in TP53 and PIK3CA alongside dynamic MCL1 amplification. The persistent activation of the PI3K-Akt pathway presents a key therapeutic vulnerability. Our findings emphasize the potential of PI3K-Akt inhibition and metastasis-specific targeting strategies for this aggressive disease.

Keywords:  PIK3CA; TP53; clinicopathological characteristics; functional enrichment analysis; metaplastic breast carcinoma; molecular characteristics; next-generation sequencing

DOI:  https://doi.org/10.2147/BCTT.S558033
Cell Death Dis. 2026 Feb 27.

ROR1-PI3K/AKT signaling drives adaptive resistance to cell cycle blockade in TP53 mutated ovarian cancer.

Juuli Raivola, Frida Rantanen, Alice Dini, Emilia Piki, Harlan Barker, Elina Multamäki, Franziska Bentz, Pia Sunkel, Aino-Maija Kiiski, Lassi Paavolainen, Astrid Murumägi, Daniela Ungureanu.

Drug resistance remains a major challenge to durable responses in ovarian cancer, the fifth leading cause of cancer-related death among women. In this study, we developed long-term resistant (lt-res, several months) pre-clinical models of two drugs inducing mitotic arrest in TP53-mutated cells: adavosertib (ADA), an investigational WEE1 inhibitor targeting the DNA damage response and currently evaluated in clinical trials, and paclitaxel (PTX), a widely used chemotherapeutic agent in cancer care targeting microtubules. Through integrated multi-omics functional profiling, we identify a shared PI3K/AKT-regulated signaling node that governs drug adaptation across all lt-res models. This node modulates the activity of DNA-damage responses and genotoxic stress to toggle between two adaptive states: activated PI3K/AKT driving a proliferative "fast-bypass" program with sustained cell cycle progression and mitotic evasion, or reduced PI3K/AKT signaling initiating a "slow-repair" state characterized by DNA damage checkpoint engagement, replication slowdown, and increased drug efflux. Notably, upregulation of receptor tyrosine kinases, such as ROR1, was observed in both ADA and PTX lt-res models with activated PI3K/AKT signaling. Targeting ROR1 with zilovertamab-vedotin, a monoclonal antibody-drug conjugate, resulted in enhanced cytotoxicity, demonstrating a new approach against recurrent drug-resistant ovarian cancer.

DOI: https://doi.org/10.1038/s41419-026-08501-x