bims-p53act 2026-02-01 papers

bims-p53act

Biomed News

on p53 mutations and anti-cancer therapy response

Issue of 2026–02–01
eleven papers selected by
Toni Martínez Bernabé, Universitat de les Illes Balears

Oncogenic p53 induces mitotic errors in lung cancer cells by recopying DNA replication forks conferring targetable proliferation advantage.
Pro-ATO/Allicin Liposomes for Dual-Pathway Targeting of p53-Mutant Tumors.
Correlation analysis of TP53 missense mutations and p53 protein expression patterns in endometrial carcinoma.
Prognostic Impact of RAS and TP53 Mutation Profiles in Metastatic Colorectal Cancer.
CP-31398 restored the functional condensates of R175H p53 by stabilizing the zinc-binding domain and 251-258 segment.
TP53 mutation predict poor prognosis in diffuse large B-cell lymphoma: a single-center study.
Marrow Microenvironmental Pathobiology and Therapeutic Opportunities for TP53-Mutated Myelodysplastic Syndrome/Acute Myeloid Leukemia.
CAR-T cell therapy in TP53-mutated CNS lymphoma: overcoming a high-risk genetic barrier.
Dietary intake of one-carbon nutrients and colorectal cancer risk according to TP53 status.
Synthetic lethality of decitabine plus ATR inhibition for TP53-mutated AML.
Genomic enrichment and functional impact of TP53 and CYLD alterations in recurrent and metastatic HPV-associated head and neck cancer.

Cell Death Differ. 2026 Jan 26.

Oncogenic p53 induces mitotic errors in lung cancer cells by recopying DNA replication forks conferring targetable proliferation advantage.

Shilpa Singh, Lilia Gheghiani, Brandon Velasco, Rebecca Frum, Steven R Grossman, Brad Windle, Sumitra Deb, Swati Palit Deb.

Mutations in tumor suppressor p53 that gain oncogenic functions (Onc-p53) are frequent in lungs and many other solid tumors often associated with chromosome aberrations. Why cells or tumors with Onc-p53 develop chromosomal aberrations and whether the abnormalities contribute to tumor growth remain elusive. Evidence in this communication demonstrate for the first time that replication stress induced by Onc-p53 triggers re-copying of DNA replication forks, which generates replication intermediates that cause persistent mitotic aberration and DNA segregation errors. Replication intermediates from re-copied replication forks induced by Onc-p53 activate ATM signaling, which stabilizes Onc-p53, reinforces its ability to upregulate replication factors for sustaining replication stress, thus generating a feedforward cycle accelerating tumor formation. In agreement with this observation our time lapse video microscopy show in real time that persistent mitotic aberration and DNA segregation errors induced by Onc-p53 confer selective growth advantage. Accordingly, human lung tumors with Onc-p53 show selection of cells with mitotic aberration during serial passages. Knock down of active replication forks reduces re-copied fork generation by Onc-p53 and specifically induces apoptotic death of lung cancer cells expressing Onc-p53 in xenograft lung tumors in cooperation with inhibitors of ATM activation, deselecting cells with Onc-p53 with mitotic errors. This communication reveals a novel mechanism which interconnects replication stress induced by Onc-p53 to its stabilization and ability to generate chromosomal aberration in lung cancer cells that both accelerate tumor growth and serve as a targetable therapeutic vulnerability. These findings will be extremely valuable for tumor-specific treatment of a high percentage of cancer patients with p53 mutation.

DOI: https://doi.org/10.1038/s41418-026-01670-4
Adv Sci (Weinh). 2026 Jan 29. e19194

Pro-ATO/Allicin Liposomes for Dual-Pathway Targeting of p53-Mutant Tumors.

Xiaoling Xu, WeiYi Cheng, Menghang Yang, Li He, WeiYe Ren, JingQuan Chen, LiTing He, Dandan Bao, Zhihong Zhu, Lixin Wang, Qinghua Yao, Ji-Gang Piao.

  Mutations in the tumor suppressor p53 disrupt DNA damage response (DDR) and drive therapeutic resistance in lung cancer. Although arsenic trioxide (ATO) can restore transcriptional activity of structural p53 mutants, its clinical application is limited by subtype selectivity and systemic toxicity. In parallel, p53 deficiency creates dependence on S/G2 checkpoints, rendering ATR a synthetic lethal target; however, allicin, a natural ATR inhibitor and hydrogen sulfide (H2S) donor, suffers from poor stability and bioavailability. Here, we developed a liposomal nanomedicine co-delivering pro-ATO (As5+) and allicin (AsAcP@LP) to integrate mutant p53 reactivation with DDR-targeted synthetic lethality. This formulation improves drug stability, pharmacokinetics, and tumor accumulation while masking allicin's odor. Upon tumor-specific release, allicin-mediated redox activation converts As5+ to cytotoxic As3+, enabling selective p53 reactivation, concurrent ATR inhibition, and H2S-amplified apoptosis. AsAcP@LP exhibits synergistic antitumor efficacy with favorable tolerability, providing a rational nanotherapeutic strategy for p53-mutant cancers.

Keywords:  DNA damage response (DDR); Lung cancer; Synthetic lethality; allicin; p53 mutation

DOI:  https://doi.org/10.1002/advs.202519194
Hum Pathol. 2026 Jan 23. pii: S0046-8177(26)00025-0. [Epub ahead of print]171 106056

Correlation analysis of TP53 missense mutations and p53 protein expression patterns in endometrial carcinoma.

Ying Yang, Shu Sun, Yun Xi, Chenyang Xu, Rui Zhu, Wenjuan Yin, Yanyan Zhan, Dan Su.

  p53 abnormality (p53 abn) subtype is a critical category in endometrial carcinoma (EC) molecular classification, yet clinical diagnosis often relies solely on p53 immunohistochemistry (IHC) staining or TP53 gene sequencing. This study aimed to explore the correlation between TP53 genotype and p53 protein expression in EC with TP53 missense mutations, as well as the clinical and prognostic significance of their discordance. A total of 253 EC specimens from Zhejiang Cancer Hospital (January 2021-November 2023) were retrospectively collected; 103 cases with isolated TP53 missense mutations were screened via next-generation sequencing (NGS) and subjected to p53 IHC. Variant interpretation revealed that six mutations in six patients were of uncertain significance. Among the remaining patients, 54 (involving 36 variants) showed concordance between IHC phenotype and genotype: high frequency mutations such as R273H, Y220C, M237I, and V272L all exhibited mutant p53 expression, whereas V31I showed wild-type expression. Another 43 patients (involving 13 variants) displayed discordance between genotype and IHC phenotype. Clinicopathological comparison revealed that the discordant group was younger (<60 years) and dominated by non-aggressive histology (all P < 0.05). The discordant group showed better survival trends than the concordant group, with no statistically significant difference in disease-free survival (DFS) (P = 0.057). In conclusion, p53 expression is heterogeneous in EC with TP53 missense mutations; gene-protein discordance correlates with distinct clinicopathological features. Integrating genetic and protein detection results is recommended for risk stratification and individualized treatment.

Keywords:  Endometrial carcinoma; Immunohistochemistry; Next-generation sequencing; TP53

DOI:  https://doi.org/10.1016/j.humpath.2026.106056
Medicina (Kaunas). 2026 Jan 09. pii: 136. [Epub ahead of print]62(1):

Prognostic Impact of RAS and TP53 Mutation Profiles in Metastatic Colorectal Cancer.

Mustafa Emre Duygulu, Elanur Karaman, Serdar Karakullukçu, Sevdegül Aydın Mungan.

  Background and Objectives: Our study aimed to investigate the effect of RAS and TP53 mutations, either alone or in combination, on survival in patients with metastatic colorectal carcinoma (mCRC). Materials and Methods: Patients diagnosed with mCRC and followed up at our center between January 2019 and November 2023, who underwent somatic mutation analysis via next-generation sequencing (NGS) testing, were retrospectively evaluated. A total of 155 patients were evaluated within the scope of the study. Patients were grouped as mutant type (m) or wild type (w) for RAS and TP53. Survival times between the groups were examined using the Kaplan-Meier method. Cox regression analysis was performed for factors with a prognostic effect on survival. Results: Among the patients, 35.4% exhibited an RASm/TP53w mutation profile, 30.9% had RASw/TP53w, 20% had RASw/TP53m, and 13.5% had RASm/TP53m. The lowest median progression-free survival (mPFS) and median overall survival (mOS) durations were observed in the RASm/TP53w group (7.3 months and 16.9 months, respectively). Median OS was significantly lower in the RASm/TP53w group compared to the RASw/TP53w group (16.9 months vs. 26.0 months, p = 0.003), whereas no significant difference was found between mPFS durations. No statistically significant difference was observed between the RASw/TP53m and RASm/TP53m groups and the RASw/TP53w group for mPFS and mOS. The RASm/TP53w mutation profile was identified as an independent prognostic factor for decreased OS in the multivariate Cox regression analysis. Conclusions: In mCRC cases with the RASm/TP53w mutation profile, the mOS was significantly lower. The RASm/TP53w mutation profile was identified as an independent prognostic factor for decreased OS. These findings are expected to contribute to the literature as real-world evidence regarding the prognostic value of different RAS and TP53 mutation combinations in mCRC.

Keywords:  RAS; TP53; metastasis; metastatic colorectal carcinoma; mutation

DOI:  https://doi.org/10.3390/medicina62010136
Colloids Surf B Biointerfaces. 2026 Jan 26. pii: S0927-7765(26)00062-7. [Epub ahead of print]262 115474

CP-31398 restored the functional condensates of R175H p53 by stabilizing the zinc-binding domain and 251-258 segment.

Yang Liu, Yuan Liu, Chang Xu, Fangming Jiang, Xiaorong Yang.

  Tumor suppressor p53 formed the droplets with the solidification tendency. Mutations in p53 could accelerate the aggregation of droplets, resulting in p53 to lose the function and/or to gain the oncogenic activity. In this study, the effects of CP-31398 on the phase behaviors of p53 mutants were explored. The results revealed that CP-31398 could inhibit the pathological aggregation of R175H p53, restored the interaction between R175H p53 and specific DNA, and promoted the formation of functional droplets. For R248W p53, CP-31398 could regulate the phase behavior but not restore the formation of functional condensates. Molecular dynamics simulations showed that CP-31398 enhanced the structural stability of R175H p53 by stabilizing the zinc-binding domain and 251-258 segment. These findings provided new insights into the molecular basis that CP-31398 restored the liquid-liquid phase separation of p53 mutant, and could offer the novel therapeutic strategy for cancers with p53 mutant.

Keywords:  CP-31398; Condensates; LLPS; R175H; R248W

DOI:  https://doi.org/10.1016/j.colsurfb.2026.115474
Ann Hematol. 2026 Jan 29. 105(2): 66

TP53 mutation predict poor prognosis in diffuse large B-cell lymphoma: a single-center study.

Haiyan Zhang, Xiang Zhang, Jinghan Wang, Xuewu Zhang, Yunfei Lv, Yanan Zhu, Xingnong Ye, Juying Wei, Min Yang, Gaixiang Xu, Chunmei Yang, Haitao Meng, Wanzhuo Xie, Jie Jin, Hongyan Tong, Wenjuan Yu.

  Whether TP53 mutation can serve as a simplified prognostic surrogate for complex genomic classifiers in diffuse large B-cell lymphoma (DLBCL) remains unclear. we comprehensively analyzed a retrospective cohort of 444 newly diagnosed DLBCL patients. TP53 mutation was an independent prognostic factor for inferior overall survival (OS) and progression-free survival (PFS) (both P < 0.001), correlating with inferior response to R-CHOP and enrichment in refractory/relapsed disease. Furthermore, multivariate analysis revealed that the adverse prognostic effect of TP53 mutation was predominantly driven by its impact within the germinal center B-cell-like (GCB) subtype, as evidenced by a significant statistical interaction. Notably, the combination of TP53 mutation and double-expression lymphoma (DEL) identified an ultra-high-risk group with synergistic poor survival. The prognostic impact was not modified by the specific protein domain, mutation burden, or gain- versus loss-of-function nature of the mutations. However, a high variant allele frequency (VAF) ≥ 53% identified a subgroup with worse survival. Finally, we adapted a p53 immunohistochemical classification from ovarian/endometrial cancer to enhance TP53 mutation prediction: overexpression (> 80%) or complete absence (< 1%) as high-risk, and heterogeneity (1%-80%) as low-risk. This approach achieved 72.5% sensitivity and 97.4% specificity, with specificity surpassed conventional ≥ 50% cutoff (P < 0.001). In conclusion, TP53 mutation is a critical, context-dependent biomarker in DLBCL, and its combination with DEL identifies a clinically actionable, ultra-high-risk group. The p53 IHC classifier shows promise as a rapid screening tool, warranting further validation.

Keywords:   TP53 mutation; Diffuse large B-cell lymphoma; Double-expression lymphoma; Germinal center B-cell-like; P53; Prognosis

DOI:  https://doi.org/10.1007/s00277-026-06821-8
Cancers (Basel). 2026 Jan 16. pii: 275. [Epub ahead of print]18(2):

Marrow Microenvironmental Pathobiology and Therapeutic Opportunities for TP53-Mutated Myelodysplastic Syndrome/Acute Myeloid Leukemia.

Cameron J Hunter, Annie P Im, Rory M Shallis.

  Mutations in TP53 inhibit p53 protective behaviors including cell cycle arrest, DNA damage repair protein recruitment, and apoptosis. The ubiquity of p53 in genome-stabilizing functions leads to an aberrant tumor microenvironment in TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Profound immunosuppression mediated by myeloid-derived suppressor cells, the upregulation of cytokines and cell-surface receptors on leukemic cells, the suppression of native immune regulator cells, and metabolic aberrations in the bone marrow are features of the TP53-mutated AML/MDS marrow microenvironment. These localized changes in the bone marrow microenvironment (BMME) explain why traditional therapies for MDS/AML, including chemotherapeutics and hypomethylating agents, are not as effective in TP53-mutated myeloid neoplasms and demonstrate the dire need for new treatments in this patient population. The unique pathophysiology of TP53-mutated disease also provides new therapeutic approaches which are being studied, including intracellular targets (MDM2, p53), cell-surface protein biologics (immune checkpoint inhibitors, BiTE therapy, and antibody-drug conjugates), cell therapies (CAR-T, NK-cell), signal transduction pathways (Hedgehog, Wnt, NF-κB, CCRL2, and HIF-1α), and co-opted biologic pathways (cholesterol synthesis and glycolysis). In this review, we will discuss the pathophysiologic anomalies of the tumor microenvironment in TP53-mutant MDS/AML, the hypothesized mechanisms of chemoresistance it imparts, and how novel therapies are leveraging diverse therapeutic targets to address this critical area of need.

Keywords:  TP53; acute myeloid leukemia; bone marrow microenvironment; chemoresistance; immunosuppression; myelodysplastic syndrome

DOI:  https://doi.org/10.3390/cancers18020275
Front Med (Lausanne). 2025 ;12 1731589

CAR-T cell therapy in TP53-mutated CNS lymphoma: overcoming a high-risk genetic barrier.

Danyang Li, Rui Liu, Zhonghua Fu, Fan Yang, Lixia Ma, Miaomiao Cao, Yuelu Guo, Biping Deng, Alex H Chang, Qinlong Zheng, Xiaoyan Ke, Kai Hu.

   Background: Central nervous system lymphoma (CNSL) is a rare but aggressive subtype of lymphoma that presents significant therapeutic challenges. The prognosis for patients with CNSL varies significantly based on several genetic factors, including TP53 mutations, which are among the most critical determinants of treatment outcomes. Chimeric antigen receptor T (CAR-T) cell therapy has shown promising results in several hematological malignancies, including B-cell lymphomas. However, its efficacy in CNSL, particularly in patients with TP53 mutations, requires further investigation.
Methods: A retrospective cohort study was conducted on 61 CNSL patients who had been treated at our institution from 2020 to 2024. The median follow-up time was 14.5 months. A total of 43 patients received CAR-T cell infusion therapy. The overall survival (OS) and progression-free survival (PFS) of patients harboring TP53 mutations (TP53+) and those with wild-type TP53 (TP53-) were compared. In addition, factors associated with patient prognosis were also identified.
Results: Among the 43 patients who received CAR-T cell therapy, 17 harbored TP53 mutations. The median age of the cohort was 51.5 years, and 51.2% of the patients (22/43) were male. The overall response rate (ORR) and the complete response rate (CRR) in the TP53+ CAR-T+ group were both 64.5% (11/17), the median OS duration was 14.07 months (95% CI 12.63-∞), and the median PFS duration was 12.77 months (95% CI 6.33-∞). In the TP53-CAR-T+ group, the ORR was 73.3% (19/26), the CRR was 69.2% (18/26), the median OS duration was 33.47 months (95% CI 11.23-∞), and the median PFS duration was 22.4 months (95% CI 6.13-∞). In the subgroup analysis, the cell-of-origin (COO) classification was a key factor influencing the long-term survival of CSNL patients; in the TP53+ group, patients with non-germinal center B-cell-like (GCB) classification had longer OS compared to the GCB subtype (p = 0.003).
Conclusion: CAR-T cell therapy is an effective treatment for CNSL patients harboring TP53 mutations and has the same efficacy as traditional treatment methods. Additionally, CAR-T cells may be more effective for TP53+ CSNL patients with a non-GCB classification.

Keywords:  CAR-T; CNSL; TME; TP53; cell therapy

DOI:  https://doi.org/10.3389/fmed.2025.1731589
JNCI Cancer Spectr. 2026 Jan 29. pii: pkag009. [Epub ahead of print]

Dietary intake of one-carbon nutrients and colorectal cancer risk according to TP53 status.

Shiori Nakano, Taiki Yamaji, Akihisa Hidaka, Taichi Shimazu, Kouya Shiraishi, Aya Kuchiba, Masahiro Saito, Fumihito Kunishima, Ryouji Nakaza, Takashi Kohno, Norie Sawada, Manami Inoue, Shoichiro Tsugane, Motoki Iwasaki.

   BACKGROUND: Accumulating evidence suggests that one-carbon nutrient intake reduces the risk of colorectal cancer (CRC), although folate fortification has been associated with a temporary increase in CRC incidence. We hypothesized that one-carbon nutrients might harbor preventive and pro-tumor effects on CRC according to tumor conditions and investigated whether the effect of one-carbon nutrients on CRC risk differs by TP53 status.
METHODS: In this prospective study of 21,708 Japanese participants, we applied a multivariable Cox proportional hazards model and examined the associations of dietary intakes of folate, vitamin B6, vitamin B12, and methionine with TP53-overexpressing (N = 192), TP53-non-overexpressing (N = 301), TP53-mutated (N = 180), and TP53 wild-type (N = 134) CRC risk defined by TP53 immunohistochemistry and target sequence.
RESULTS: Vitamin B12 and methionine intakes were not associated with any CRC subtypes defined by TP53 status. Meanwhile, folate intake was marginally associated with decreased TP53-mutated CRC risk (hazard ratio [HR] with 95% confidence interval [CI] for the highest folate intake quartile compared with the lowest: 0.82 [0.46-1.45]) and increased TP53 wild-type CRC risk (HR: 1.50 [0.78-2.90]). A heterogeneous effect of folate on CRC subtypes was detected (Pheterogeneity= 0.03 between TP53 mutation statuses). In women, the association between vitamin B6 and CRC also differed by TP53 mutation status (Pheterogeneity= 0.007). The HR of vitamin B6 was 0.71 [0.30-1.67] for TP53-mutated CRC and 3.89 [1.79-8.49] for TP53 wild-type CRC. However, no heterogeneous effects were observed between TP53 expression statuses.
CONCLUSION: This study supports the hypothesis that the effect of one-carbon nutrient intake on CRC differs according to tumor conditions.

Keywords:  Colorectal cancer; Dietary intake; Nutrition; One-carbon metabolism; TP53

DOI:  https://doi.org/10.1093/jncics/pkag009
Blood Adv. 2026 Jan 29. pii: bloodadvances.2025018369. [Epub ahead of print]

Synthetic lethality of decitabine plus ATR inhibition for TP53-mutated AML.

Jeremy T Baeten, Sumedha Agashe, Imene Tabet, Jack T Wooldridge, Amber Carter, Jamie N Butler, Christopher A Miller, Nichole M Helton, Annabel Quinet, Kimberly B Johansson, Yichan Yang, Geoffrey L Uy, Alessandro Vindigni, Daniel C Link.

TP53 mutations are found in 10-15% of myeloid neoplasms and are associated with a dismal prognosis. Although hypomethylating agents, such as decitabine, are active in TP53-mutated myeloid neoplasms (TP53-MN), mutation clearance is rarely complete and nearly all patients relapse. Molecular determinants of response to hypomethylating agents in TP53-MN are poorly understood. Here, we show that decitabine induces replicative stress with decreased replication fork progression, induction of single-strand DNA breaks, and activation of the ATR pathway. Resolution of decitabine-induced replication stress is impaired in TP53-mutated acute myeloid leukemia (AML) cells, representing a potential therapeutic vulnerability. Indeed, the combination of decitabine and ATR inhibition (ATRi) induces synthetic lethality that is selective for TP53-AML and due, in part, to induction of mitotic catastrophe. Interestingly, this synergistic lethality was not observed with azacitidine or treatment with GSK3685032, a potent DNMT1 inhibitor, both of which produce a comparable level of global hypomethylation to decitabine. Treatment with decitabine and ATR inhibitor reduces leukemia burden and prolongs survival in in vivo mouse models of TP53-mutated AML. Collectively, these show that TP53 loss generates a selective vulnerability to decitabine-induced replication stress, with the combination of ATR inhibition and decitabine showing promise as a new therapeutic approach for TP53-MN.

DOI: https://doi.org/10.1182/bloodadvances.2025018369
Clin Cancer Res. 2026 Jan 28.

Genomic enrichment and functional impact of TP53 and CYLD alterations in recurrent and metastatic HPV-associated head and neck cancer.

Manu Prasad, Alex T Cheng, Marcel Mayer, Louis Jansen, Elizabeth Koh, Zaineb Nadeem, Gopika Sivan Pillai, Joris Vos, Fengshen Kuo, Karena Zhao, Hannah J Sfreddo, Andrew Lee, Siqi Chen, Jennifer Schloss, Xinzhu Deng, Swati Jain, Daniel Muldoon, Chaitanya Bandlamudi, Jens Peter Klussmann, Thomas J Ow, Alan L Ho, Nancy Y Lee, Nadeem Riaz, Richard J Wong, Ian Ganly, Nora Katabi, Luc G T Morris.

PURPOSE: Recurrent and metastatic human papillomavirus-associated head and neck squamous cell carcinoma (R/M HPV+ HNSCC) remains largely incurable, with genetic drivers incompletely defined. We profiled the genetic landscape of R/M HPV+ HNSCC, and functionally characterized genetic alterations strongly enriched in this cancer type.
EXPERIMENTAL DESIGN: We identified genetic alterations uniquely enriched in 159 R/M HPV+ tumors. High-priority alterations were functionally modeled, examining proliferation, clonogenicity, migration/invasion, apoptosis, therapy response, in vivo growth, and metastasis, and immune contexture.
RESULTS: Compared with HPV+ primary tumors, R/M HPV+ tumors were enriched for TP53 mutations (pre-specified FDR threshold met; OR 6.23; p=.02) and associated with poorer survival. Within R/M disease, CYLD alterations were specific to HPV+ tumors (21% vs 0% in HPV-). TP53 mutations were predominantly clonal and associated with whole genome duplication. Expression of TP53 GOF mutants (R175H, G245C, R273C) in HPV+ HNSCC cells increased clonogenic survival, migration/invasion, lung metastatic burden in vivo, and cisplatin IC50, without altering radiation sensitivity. CYLD knockdown accelerated cellular growth yet increased radiosensitivity. Transcriptomic analyses linked CYLD loss to NF-κB/TNF-α pathway activation, a T-cell-inflamed microenvironment, and checkpoint upregulation.
CONCLUSIONS: R/M HPV+ HNSCC is genomically and functionally shaped by 2 axes with therapeutic implications: TP53 gain-of-function mutations promote metastatic phenotypes and cisplatin resistance, while CYLD loss defines an HPV-specific subset with enhanced radiation sensitivity and immune activation. These data support using TP53 and CYLD as predictive biomarkers to guide investigation into precision strategies for systemic therapy choices, p53-targeted/Wee1 strategies, and radiotherapy-immunotherapy combinations in high-risk or R/M HPV+ HNSCC.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-3972