bims-p53act 2026-04-05 papers

bims-p53act

Biomed News

on p53 mutations and anti-cancer therapy response

Issue of 2026–04–05
eleven papers selected by
Toni Martínez Bernabé, Universitat de les Illes Balears

Clinical impact of TP53 mutation status on survival outcomes in metastatic colorectal cancer.
Correlation of TP53 Mutations With p53 Expression and Ki-67 Index in Pulmonary Large Cell Neuroendocrine Carcinomas.
Clinical significance of TP53 mutations in patients with acute myeloid leukemia: the HM-SCREEN-JAPAN 01/02 study.
Mutant p53 Directs PARP to Regulate Replication Stress and Drive Breast Cancer Metastasis.
Targeting mutant p53 in cancer: from mechanistic insights to therapeutic strategies.
The Moving Target: Cis-Mutation-Driven Resistance to p53-Y220C Reactivator.
Medulloblastoma response to mevalonate pathway inhibition is independent of p53 status.
Reactivating p53 mutants selectively in patients.
Genotoxic Chemotherapy in Li-Fraumeni Syndrome: Molecular Mechanisms, Clinical Consequences, and Alternative Therapeutic Strategies.
Presence of IDH2 and TP53 mutations significantly reduces survival of patients with chondrosarcoma.
CBC3T-3: a novel patient-derived cisplatin-resistant distal cholangiocarcinoma cell line harboring multiple TP53 missense mutations.

Rev Assoc Med Bras (1992). 2026 ;pii: S0104-42302026000102217. [Epub ahead of print]72(1): e20250998

Clinical impact of TP53 mutation status on survival outcomes in metastatic colorectal cancer.

Oğuzhan Yıldız, Hakan Şat Bozcuk, Melek Karakurt Eryılmaz, Murat Araz, Ali Fuat Gürbüz, Mahmut Selman Yıldırım, Mehmet Artaç.

BACKGROUND: The prognostic value of TP53 mutations in metastatic colorectal cancer remains unclear owing to inconsistent findings in the literature. Given its central role in tumor biology, clarifying the impact of TP53 status on survival outcomes is clinically relevant.
METHODS: This retrospective cohort study included 115 patients with metastatic colorectal cancer who underwent TP53 mutational analysis using next-generation sequencing (KAPA HyperPETE Pan Cancer Panel). Eligible patients were aged ≥18 years, had histologically confirmed metastatic colorectal cancer, and received first-line systemic therapy. Patients with incomplete clinical or molecular data were excluded. Based on mutation profiles, those with RAS or BRAF mutations received anti-VEGF therapy, whereas patients with wild-type tumors received anti-EGFR treatment. Patients were stratified according to TP53 mutation status to evaluate differences in clinical outcomes.
RESULTS: Among the 115 patients included, 78 (67.8%) harbored TP53 mutations and 37 (32.2%) had wild-type TP53. The median progression-free survival was significantly longer in the TP53-mutant group (18.6 vs. 10.0 months; p=0.002). The median overall survival was also numerically longer in the TP53-mutant group (32.9 vs. 30.3 months), although this difference was not statistically significant (p=0.114). In the univariate analysis, TP53 mutation was associated with improved progression-free survival (HR 0.479; 95%CI 0.294-0.779; p=0.003). This association remained independently significant in the multivariate analysis (HR 0.477; 95%CI 0.289-0.787; p=0.004). None of the other variables consistently predicted survival.
CONCLUSION: TP53 mutations appear to be an independent prognostic marker for prolonged progression-free survival in patients with metastatic colorectal cancer. Although the difference in overall survival was not statistically significant, these findings warrant further validation in prospective studies to confirm the prognostic utility of TP53 in therapeutic stratification.

DOI: https://doi.org/10.1590/1806-9282.20250998
APMIS. 2026 Apr;134(4): e70189

Correlation of TP53 Mutations With p53 Expression and Ki-67 Index in Pulmonary Large Cell Neuroendocrine Carcinomas.

Martin Stampe, Jonas Smidt, Linea Melchior, Morten Grauslund, Birgitte Federspiel, Eric Santoni-Rugiu, Thomas Hartvig Lindkær Jensen.

  This study explores the locations and distribution of mutations in the exons of the TP53 gene in pulmonary large cell neuroendocrine carcinomas (LCNEC) and the corresponding expression of p53 as well as the Ki-67 proliferation index. Real-world data from routine diagnostics were collected retrospectively from 149 consecutive cases of pulmonary LCNEC. They included next-generation sequencing (NGS) of the TP53 gene along with evaluation of p53 and Ki-67 expression with immunohistochemistry (IHC). Abnormal p53 expression was defined as strong positive nuclear reaction in more than 20% of the tumor cells or complete absence of immunostaining in tumor cells. Both p53 expression and Ki-67 proliferation index correlated with TP53 mutations. In addition, a statistically significant increase in Ki-67 expression was found for cases with abnormal staining of p53 compared to samples with normal staining. We found that IHC staining for p53 can identify TP53 mutations in pulmonary LCNEC with an overall concordance of 76.6%. Moreover, both pathological patterns of p53 immunostaining and NGS-detected TP53 mutations were associated with higher Ki-67 proliferation indices.

Keywords:  Ki‐67; TP53 mutations and p53 expression; immunohistochemistry; pulmonary large cell neuroendocrine carcinomas; thoracic pathology

DOI:  https://doi.org/10.1111/apm.70189
Int J Hematol. 2026 Mar 31.

Clinical significance of TP53 mutations in patients with acute myeloid leukemia: the HM-SCREEN-JAPAN 01/02 study.

Fumiya Ogasawara, Yosuke Minami, SungGi Chi, Tomoaki Ueda, Kentaro Fukushima, Kensuke Kojima.

  Mutant TP53 (mTP53) variants are diverse, and residual wild-type p53 function (functional, non-functional), gain-of-function (GOF) mTP53, and the number of mTP53 (single-hit, multi-hit) can affect prognosis. We used next-generation sequencing to evaluate the association between qualitative and quantitative mTP53 abnormalities and overall survival (OS) in 330 patients with acute myeloid leukemia (AML) enrolled in the Japanese multicenter study HM-SCREEN-JAPAN 01/02. Patients with single- and multi-hit mTP53 had a worse prognosis than patients with wild-type TP53 (median OS: 16.1 months vs. 7.5 months vs. 41.6 months). Patients with multi-hit mTP53 had a worse prognosis (P = 0.011). Patients with both mTP53 and complex karyotype (CK) had a worse prognosis than patients with either mTP53 or CK (median OS: 7.6 months vs. 15.0 months vs. 18.9 months; P = 0.03). Residual function did not affect prognosis in patients with single-hit mTP53 (median OS: 24.9 months vs. 16.1 months; P = 0.985), and prognosis did not differ between patients with GOF mTP53 and those with non-GOF mTP53 (median OS: 9.5 months vs. 9.8 months; P = 0.913). Quantitative abnormalities in the TP53 gene affected prognosis, suggesting that qualitative abnormalities did not.

Keywords:   TP53 mutations; Acute myeloid leukemia; Prognosis; Quality; Quantity

DOI:  https://doi.org/10.1007/s12185-026-04192-4
bioRxiv. 2026 Mar 28. pii: 2026.03.26.713220. [Epub ahead of print]

Mutant p53 Directs PARP to Regulate Replication Stress and Drive Breast Cancer Metastasis.

Gu Xiao, George K Annor, Katherine W Harmon, Valery Chavez, Fayola Levine, Samuel Ahuno, Mohamed I Atmane, Samantha St Jean, Florencia P Madorsky Rowdo, Pamella Leybengrub, AnnMarie Gaglio, Viola Ellison, Divya Venkatesh, Siyu Sun, Taha Merghoub, Benjamin Greenbaum, Olivier Elemento, Melissa B Davis, Olorunseun Ogunwobi, Jill Bargonetti.

TP53 mutations occur in 80-90% of triple-negative breast cancers (TNBCs) and drive genomic instability and metastatic progression. Poly (ADP-ribose) polymerase (PARP) is critical for DNA repair and replication fork stability. How oncogenic signaling influences PARP function to sustain proliferation during replication stress remains unclear. Mutant p53 (mtp53) R273H associates tightly with chromatin, forms complexes with PARP, and enhances PARP recruitment to replication forks [1-3]. The C-terminal region of mtp53 mediates mtp53-PARP and mtp53-Poly (ADP-ribose) (PAR) interactions that facilitate S phase progression [4, 5]. The PARP inhibitor talazoparib (TAL) combined with the alkylating agent temozolomide (TMZ) produces synergistic cytotoxicity selectively in mtp53, but not wild-type p53 (wtp53), breast cancer cells and organoids. Herein we evaluated the mechanism of mtp53-associated cell death and tested if this could translate to a preclinical xenograft model. We found that TMZ+TAL treatment induced elevated cleaved PARP and γH2AX and reduced the metastasis-promoting oncoprotein MDMX. In orthotopic xenografts expressing mtp53 R273H, but not wtp53, combination therapy significantly decreased circulating tumor cells (CTCs) and lung metastases. Transcriptomic profiling of tumors from combination treated animals demonstrated downregulation of MDMX , VEGF, and NF-κB , consistent with the observed suppression of CTCs and lung metastasis, and increased γH2AX, indicative of replication stress in mtp53 xenografts. Inhibition of metastasis was also observed in mtp53 R273H WHIM25 and p53-undetectable WHIM6 TNBC patient-derived xenografts (PDX). The mtp53 C-terminal domain (347-393) demonstrated a critical tumor promoting function, as CRISPR-mediated deletion impaired replication fork progression, tumor growth, and metastatic dissemination. DNA fiber combing showed that expression of full-length mtp53 R273H, but not C-terminal deleted Δ347-393, supported sustained single-stranded DNA gaps (ssGAPs) following Poly (ADP-ribose) glycohydrolase (PARG) inhibition. These findings support that mtp53 uses C-terminal amino acids to exploit PARP to enable replication stress adaptation and that mtp53 is a predictive biomarker for combined PARP inhibitor and DNA damaging therapies targeting TNBC.
Significance statement: TP53 mutations are the most common genetic alterations in TNBC and a major driver of replication stress and metastasis. This study shows that missense mutant p53 uses C-terminal amino acids to reprogram PARP activity to maintain tumor cell survival under replication stress. We demonstrate that p53 status governs the response to combined PARP inhibitor (PARPi) and DNA-damaging chemotherapy, establishing an additional molecular basis beyond BRCA1 mutations for treating TNBC with PARPi therapy. These findings reveal a previously unrecognized mechanism by which the mutant p53-PARP axis enables replication stress tolerance and drives cancer metastasis. We show mutation of p53 in TNBC provides an additional biomarker-guided framework to improve PARPi therapeutic outcomes.

DOI: https://doi.org/10.64898/2026.03.26.713220
Cell Mol Biol Lett. 2026 Mar 31.

Targeting mutant p53 in cancer: from mechanistic insights to therapeutic strategies.

H Helena Wu, Sarah Leng, David D Eisenstat, Consolato Sergi, Roger Leng.



Keywords:  Cancer progression; Cancer therapy; Gain-of-function; Mutation; p53 tumor suppressor

DOI:  https://doi.org/10.1186/s11658-026-00907-x
Cancer Discov. 2026 Apr 01. 16(4): 620-622

The Moving Target: Cis-Mutation-Driven Resistance to p53-Y220C Reactivator.

Yanqing Liu, Wei Gu.

The study by Fece de la Cruz, Varkaris, and colleagues uncovered a critical mechanism underlying resistance to the p53-Y220C reactivator rezatapopt in the PYNNACLE clinical trial. Specifically, rezatapopt treatment was shown to select for secondary mutations in the TP53 gene on the Y220C-mutant background, thereby abrogating its therapeutic efficacy. See related article by Fece de la Cruz et al., p. 677.

DOI: https://doi.org/10.1158/2159-8290.CD-26-0153
Biol Direct. 2026 Apr 01.

Medulloblastoma response to mevalonate pathway inhibition is independent of p53 status.

Charley Comer, Christopher Edwards, Sabrina Caporali, Yuhui Lu, Alessio Butera, David Michod, Andreas J Gruber, Ivano Amelio, Maria Victoria Niklison-Chirou.

  Medulloblastoma (MB) is the most common primary solid paediatric brain tumour. It arises in the cerebellum, the part of the brain responsible for equilibrium and coordination. Molecular profiling has identified four MB subgroups named Wingless (WNT), Sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), each of which possesses distinct genetic backgrounds and clinical outcomes. The treatment of MB requires intensive multimodal therapy that is associated with significant long-term side effects. Despite this necessary aggressive approach, MB remains fatal in approximately 30% of patients due to tumour recurrence and/or metastatic spread to the spinal cord. Thus, there is an urgent need for novel, less toxic and effective therapies for MB. The tumour-suppressor p53 is mutated in up to 30% of SHH-MB tumours and is associated with significantly poorer patient outcomes. Mutations in p53 have been acknowledged to confer oncogenic "gain-of-function" properties, including activation of the mevalonate pathway (MVP), which drives cholesterol and isoprenoid biosynthesis. MB is sensitive to inhibition of the MVP by treatment with simvastatin, leading us to hypothesise that targeting the mutant p53 (mutp53)-MVP axis could further sensitise mutp53 SHH-MB to statins. In this study, we show that silencing p53 does not alter simvastatin sensitivity in either mutp53 SHH-MB or wild-type p53 G3-MB cells. Moreover, p53 silencing had no effect in the mRNA expression of the key MVP enzymes 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), mevalonate kinase (MVK), mevalonate decarboxylase (MVD), and farnesyl diphosphate synthase (FDPS). Silencing p53 also failed to affect simvastatin-induced cell cycle arrest or impact the sensitivity of MB cells treated with simvastatin in combination with hypoxia, X-ray or azacitidine, an epigenetic therapy with DNA methyltransferase inhibition. Collectively, our findings indicate that MVP function is independent of p53 in MB.

Keywords:  Cholesterol; Medulloblastoma; Metabolism; Mutant p53; p53

DOI:  https://doi.org/10.1186/s13062-026-00765-9
Cancer Cell. 2026 Apr 02. pii: S1535-6108(26)00163-7. [Epub ahead of print]

Reactivating p53 mutants selectively in patients.

Shuo Chen, H Michael Shepard, Min Lu.

As the most frequently mutated protein across cancers, the tumor suppressor protein p53 is inactivated by the most extensive array of different mutations. Targeting a frequent p53 mutant with the reactivator rezatapopt, recent findings published in the New England Journal of Medicine mark an encouraging step toward clinical utility.

DOI: https://doi.org/10.1016/j.ccell.2026.03.009
Curr Pharm Des. 2026 Mar 25.

Genotoxic Chemotherapy in Li-Fraumeni Syndrome: Molecular Mechanisms, Clinical Consequences, and Alternative Therapeutic Strategies.

Antonio Ruggiero, Giorgio Attinà.

   INTRODUCTION: Li-Fraumeni syndrome is an extremely rare autosomal dominant hereditary cancer predisposition disorder that is brought about by pathogenic germline TP53 variants. Insiders are unusually susceptible to malignancies of various organ systems and may also suffer from increased toxicity to DNA, damaging cytotoxic agents as a result of defective cellular damage response pathways. This study aims to analyze the DNA-damaging effects of commonly used cytotoxic chemotherapeutic agents in an LFS population, reveal the molecular pathophysiology underlying treatment, related secondary cancer development, and determine the clinical applicability of alternative non-DNA-damaging therapeutic options.
METHODS: We searched PubMed and MEDLINE for studies published from 1969 up to January 2025. We focused on articles in English that discussed Li-Fraumeni patients, treatment outcomes, and the biology behind their cancer risks. Articles about non-TP53 hereditary syndromes and purely preclinical studies without clinical relevance were excluded. The narrative synthesis method brings together various types of studies (case series, cohort studies, clinical trials, molecular studies) for a clinical context that is not suitable for a systematic review methodology, thus presenting a more comprehensive picture.
RESULTS: Clinical evidence reveals an increased risk of secondary malignancy in Li-Fraumeni syndrome patients, especially after radiation therapy. There is less data on the risks of chemotherapy, but both clinical observations and preclinical models indicate an increased likelihood of secondary malignancies. The size of the risk depends on the type, stage, and patient age, as well as the treatment used. Therapeutic agents such as p53 pathway modulators that do not damage DNA, precision, targeted drugs, and immune-based therapies offer both therapeutic efficacy and reduced carcinogenic exposure potential.
DISCUSSION: Li-Fraumeni syndrome requires a personalized risk assessment to balance the risk of cure with the likelihood of secondary malignancies. Among all treatments, radiation therapy has shown the strongest and most consistent association with the development of subsequent cancers. On the other hand, the risks from chemotherapy, specific treatments are still not well understood because of the limitations of the methodologies used when studying rare diseases. Aggressive malignancies should be treated first and foremost with treatment efficacy in mind, and non-genotoxic treatments should be considered mainly in cases where they are equally effective as other options, especially in pediatric patients who have a longer lifetime cancer risk.
CONCLUSION: Therapeutic management of Li-Fraumeni syndrome should be based on individualized riskbenefit analysis, weighing the potential for cure against the possibility of long-term risks. Treatment with radiation therapy has been more frequently and consistently linked to the development of secondary malignancies, but the treatment efficacy should usually be given priority even over chemotherapy-related theoretical concerns, particularly in cases of aggressive or life-threatening malignancies. Intensified surveillance protocols allow for earlier detection of cancer, and new non-genotoxic drugs thus far represent viable therapeutic options for certain patients and tumor types.

Keywords:  DNA damage; Li-Fraumeni syndrome; TP53 mutations; cytotoxic chemotherapy; p53 pathway modulation; precision oncology; targeted therapeutics.; treatment-induced malignancy

DOI:  https://doi.org/10.2174/0113816128434078260202061518
Cancer. 2026 Apr 01. 132(7): e70376

Presence of IDH2 and TP53 mutations significantly reduces survival of patients with chondrosarcoma.

Anne Weidlich, Klaus-Dieter Schaser, Tareq A Juratli, Jessica Pablik, Sven Märdian, Kathrin Hauptmann, Philipp Schwabe, Stephan Richter, Hagen Fritzsche.

   BACKGROUND: Chondrosarcoma (CS) has a prognosis largely influenced by tumor grade. Although IDH mutations have been reported in CS, impact on patient`s survival remains controversial. This study aims to assess prognostic relevance of IDH mutations on disease-specific survival (DSS), metastasis-free survival (MFS), and local recurrence-free survival (RFS), in a large cohort of CS patients.
METHODS: The authors retrospectively analyzed CS samples from patients treated at two German musculoskeletal tumor centers. Tumor-specific mutations, including IDH, TP53, TERT promoter, and CDKN2A/B, were identified through DNA isolation and next-sequencing. Molecular findings were correlated with oncologic outcomes to evaluate their prognostic significance.
RESULTS: A total of 109 patients (53 females, 56 males; median age, 57 (16-89) years) were included. Tumor grades were G1/ACT (39%), G2 (41%), and G3/dedifferentiated (10%). Median follow-up was 3.8 years with mortality of 17%. IDH mutations were detected in 59% (IDH1: 64%, IDH2: 36%), with dedifferentiated CS showing highest IDH mutation rate (91%), particularly IDH2. IDH2-mutations were associated with significantly worse DSS compared to IDH-wild-type or IDH1-mutated tumors, independent of tumor grade. Specifically, IDH1-R132C mutation correlated with significantly improved DSS compared to R132G, and IDH2-R172S variant showed longest DSS and MFS, whereas IDH2-R172T was linked to significant poor outcomes. In multivariable analysis, IDH2 and TP53 mutations were independent predictors of worse survival.
CONCLUSION: IDH2 and TP53 mutations are enriched in dedifferentiated CS and are significant, independent predictors of adverse survival, regardless of tumor grade. These findings support IDH2 mutation status as clinically meaningful prognostic biomarker that may allow risk stratification and clinical decision-making in CS patients.

Keywords:  IDH mutation; IDH2; TP53; chondrosarcoma; sarcoma; survival

DOI:  https://doi.org/10.1002/cncr.70376
Hum Cell. 2026 Mar 31. pii: 56. [Epub ahead of print]39(4):

CBC3T-3: a novel patient-derived cisplatin-resistant distal cholangiocarcinoma cell line harboring multiple TP53 missense mutations.

Jiahui Xi, Mingzhen Bai, Ruyang Zhong, Chongfei Huang, Ruoshui An, Long Gao, Haidong Ma, Liang Tian, Jinyu Zhao, Ningzu Jiang, Xiang He, Leiqing Wang, Zihe Dong, Ping Yue, Yanyan Lin, Zhongtian Bai, Wenbo Meng.

  Distal cholangiocarcinoma (dCCA) is a malignant tumor characterized by a challenging diagnosis, high invasiveness, and extremely poor prognosis. Research on dCCA is limited by the scarcity of reliable patient-derived preclinical tumor models. This study established a novel human distal cholangiocarcinoma cell line, CBC3T-3, and systematically characterized its biological properties, genomic features, and potential for clinical application. This cell line was extracted from postoperative distal cholangiocarcinoma tumor from a 54-year-old male patient. It was stably passaged (> 50 generations) through primary culture and condition optimization, preserving the same pathology as that of the primary tumor. Whole-exome sequencing (WES) confirmed somatic mutations, tumor mutation burden, single-sample clonal structure, driver genes, and drug resistance genes in CBC3T-3 cells, revealing their genomic characteristics. Functional assays demonstrated that CBC3T-3 cells exhibit strong capabilities for proliferation, migration, and invasion in vitro. In a subcutaneous xenograft model in immunodeficient mice, palpable tumor nodules developed within 4 weeks, reflecting the clinical characteristics of rapidly progressive disease. Drug sensitivity analysis revealed that, compared with TFK-1 cells, CBC3T-3 cells presented significantly greater responses to paclitaxel, gemcitabine, and oxaliplatin but relatively poor responses to 5-FU and cisplatin. The integration of drug resistance gene findings from WES suggests that TP53 missense mutations may mediate primary resistance to cisplatin. The establishment of the CBC3T-3 cell line enhances the research toolkit for dCCA. Its genomic characteristics and functional plasticity provide a reliable preclinical tumor model for developing precision therapies and investigating drug resistance mechanisms.

Keywords:   TP53 missense mutation; Cell line; Cisplatin; Distal cholangiocarcinoma; Drug resistance

DOI:  https://doi.org/10.1007/s13577-026-01369-1