bims-p53act 2026-02-08 papers

Biomacromolecules. 2026 Feb 02.

Bile Acid-Induced Aggregation and Phase Separation of Mutant p53 Leads to Doxorubicin Sequestration.

Harpreet Kaur, Devansh Swadia, Ishani Sharma, S M Rose, Sharmistha Sinha.

Mutations in the tumor suppressor p53, particularly the R273 mutation, are major drivers of poor prognosis and treatment resistance in colorectal cancer (CRC). Additionally, reports have recently shown that environmental factors and metabolites within the tumor microenvironment act together to drive and compound tumor progression. This study investigates the interactions between secondary bile acids, lithocholic acid (LCA), and deoxycholic acid (DCA), and mutant p53 in CRC. We show that while the secondary bile acids have a minimal effect on wild-type p53, it significantly promotes the aggregation of the R273H and R273C mutant variants, an effect that is markedly enhanced in the presence of the chemotherapy drug doxorubicin in cell lines. Our biophysical studies demonstrate that the DNA binding is compromised in mutant p53 and is completely lost in the presence of the bile acids and doxorubicin. Further, we show that LCA binds to mutant p53 with high affinity, inducing the formation of large oligomeric assemblies and biomolecular condensates. Binding studies reveal stronger interactions between the bile acids and mutant p53, resulting in increased aggregation, as confirmed by imaging studies. Additionally, bile acids induce biomolecular condensate formation in mutant p53, sequestering doxorubicin within these structures and suggesting a mechanism for chemoresistance. These findings highlight the role of bile acids in promoting mutant p53 aggregation and therapy resistance, suggesting potential new therapeutic targets for p53 mutant CRC.

DOI: https://doi.org/10.1021/acs.biomac.5c01993

Technol Cancer Res Treat. 2026 Jan-Dec;25:25 15330338261420099

A Retrospective Study of the Correlation Between Next-Generation Sequencing and Immunohistochemical Detection of TP53 in Colorectal Cancer.

Jingjing Wu, Haifeng Yu, Shanshan Huang, Xiangna Chen.

IntroductionThis retrospective study aimed to investigate the correlation between TP53 identified via next-generation sequencing (NGS) and p53 expression in colorectal adenocarcinoma (CRC), as assessed by immunohistochemistry (IHC). Additionally, we characterized p53 IHC staining patterns and sought to determine the optimal threshold for p53 expression as a surrogate for TP53 mutation status.MethodsIn this retrospective cohort analysis, we included 294 archived surgically resected CRC specimens from patients who did not receive preoperative chemotherapy were analyzed. All data were collected from pathology database and electronic medical records. TP53 mutations were identified using NGS, and p53 expression was evaluated by IHC. The correlation between mutation status and IHC staining patterns was assessed, and sensitivity and specificity were calculated.ResultsThe TP53 mutation rate was 78.2%, comprising missense (68.4%), nonsense (12.4%), frameshift (11.0%), and splice-site (8.3%) mutations. Missense mutations were associated with nuclear p53 staining, while frameshift mutations mostly showed loss of expression. Nonsense and splice-site mutations exhibited diverse patterns, including loss of expression, nuclear staining with/without cytoplasmic staining, or cytoplasmic staining alone. Among cases with loss of p53 expression, the TP53 mutation rate was 88.9%. When the proportion of strong p53-positive cells exceeded 55%, the missense mutation-positivity rate increased significantly (P < 0.05). The sensitivity and specificity of p53 IHC in predicting TP53 mutations were 92.3% and 94.8%, respectively.ConclusionsCRC predominantly exhibited missense TP53 mutations. p53 IHC revealed diverse expression patterns, including overexpression, complete loss, cytoplasmic staining, and normal-type patterns. Strong p53 expression (>55%) correlated closely with TP53 missense mutations, supporting IHC as a reliable surrogate. However, cases showing loss of p53 expression should undergo gene sequencing to confirm mutation status.

Keywords: TP53; colorectal adenocarcinoma; immunohistochemistry; next-generation sequencing; threshold

DOI: https://doi.org/10.1177/15330338261420099

Clin Exp Med. 2026 Feb 02. 26(1): 128

Novel antagonist APG-115 targets MDM2-p53 to induce p53-mediated apoptosis and radiosensitization in colorectal cancer.

HanJie Yi, YongQing Han, Xia Wang, Qing Li, Le Xiong, ShanFeng Li.

Colorectal cancer remains a major global health burden, and treatment outcomes for advanced disease are still unsatisfactory. APG-115 is a next-generation small-molecule MDM2 inhibitor developed in China that restores wild-type p53 activity. However, its therapeutic potential in colorectal cancer has not been fully explored. APG-115's impact on colorectal cancer cells was evaluated through CCK-8 assays and AnnexinV-FITC/PI staining. The dependence of APG-115 activity on p53 status was assessed in p53-knockdown cell lines. In vivo, the antitumor efficacy and radiosensitizing effects of APG-115 were evaluated in nude-mouse xenograft models. APG-115 exerted a potent inhibitory effect on the proliferation of p53 wild-type colorectal cancer cell lines LOVO, RKO, and HCT116, while showed no significant impact on p53-mutant lines. In wild-type cells, APG-115 induced apoptosis in a dose-dependent manner and caused G0/G1 cell-cycle arrest. APG-115 significantly upregulated p53 and its downstream targets (MDM2, p21, PUMA), whereas these effects were absent in p53-mutant or p53-knockdown cells. In vivo, APG-115 suppressed RKO tumor growth in a dose-dependent manner, accompanied by increased p53, MDM2 and p21 expression and reduced Ki-67. Immunofluorescence further confirmed enhanced apoptosis following treatment. Importantly, the combination of APG-115 with radiotherapy significantly promoted apoptosis, decreased the S-phase proportion, and increased G2-phase arrest in p53 wild-type cells. Radiosensitization was abolished in p53-knockout RKO xenografts, confirming the requirement of an intact MDM2-p53 pathway. APG-115 effectively inhibits proliferation, induces apoptosis, and enhances radiosensitivity in p53 wild-type colorectal cancer. These findings support APG-115 as a promising therapeutic candidate for colorectal cancers retaining functional p53.

Keywords: APG-115; Apoptosis; Colorectal cancer; MDM2-p53; Radiotherapy

DOI: https://doi.org/10.1007/s10238-026-02049-y

ESMO Gastrointest Oncol. 2025 Sep;9 100221

Real-world evidence of chemotherapy effects in advanced pancreatic ductal adenocarcinoma: prognostic significance of TP53 status in gemcitabine plus nab-paclitaxel therapy.

M Sugimori, A Hirotani, H Yamazaki, M Oshi, K Kawashima, H Tsuchiya, Y Kanemaru, Y Suzuki, S Onodera, H Miwa, A Nozaki, K Sugimori, C Kunisaki, M Kudo, M Morimoto, S Maeda.

Background: Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX (FFX) therapies are widely used to treat advanced pancreatic ductal adenocarcinoma (PDAC). This study aimed to identify the prognostic factors associated with these regimens, focusing on key genomic alterations in the 'Big Four' genes (KRAS, TP53, CDKN2A, and SMAD4).
Materials and methods: This retrospective observational study analysed real-world data from 5205 PDAC patients registered in the national database, Center for Cancer Genomics and Advanced Therapeutics (C-CAT), who underwent comprehensive genomic profiling between June 2019 and December 2023 in Japan. Clinical characteristics and genomic alterations were analysed. Time to progression (TTP) was compared between patients treated with GnP or FFX as first-line therapy. Gene alterations were classified as truncating or missense mutations to assess prognostic relevance.
Results: GnP was more frequently selected than FFX as first-line treatment (2315 versus 1181). FFX was more commonly used in younger, male patients without prior adjuvant therapy. After matching for age, sex, and adjuvant history, GnP demonstrated superior TTP compared with FFX (median TTP: 6.0 versus 5.5 months, P = 0.019). In the GnP group, TP53 alterations were associated with significantly shorter TTP compared with wild-type TP53 (median TTP: 5.8 versus 7.0 months; P < 0.0001). Furthermore, truncating TP53 mutations were linked to shorter TTP than missense mutations (median TTP: 5.3 versus 5.9 months; P = 0.021).
Conclusions: In Japanese real-world data, GnP showed superior TTP compared with FFX for advanced PDAC. TP53 status may serve as a prognostic biomarker in patients receiving GnP therapy.

Keywords: gemcitabine plus nab-paclitaxel therapy; genomic profiles; leucovorin, fluorouracil, irinotecan, and oxaliplatin therapy; pancreatic ductal adenocarcinoma; time to progression; tumour protein p53 mutations

DOI: https://doi.org/10.1016/j.esmogo.2025.100221

Exp Hematol Oncol. 2026 Feb 03. 15(1): 15

Single-cell profiling reveals reprogrammed hierarchy and disrupted immune-stromal ecosystem in TP53-mutated AML.

BACKGROUND: TP53-mutated acute myeloid leukemia (AML) represents one of the most adverse-risk subtypes of AML, yet the mechanisms underlying its resistance and relapse remain poorly defined.
METHODS: We performed single-cell RNA sequencing on bone marrow samples from 30 de novo AML patients (11 TP53-mutated, 19 TP53-wild-type) and systematically analyzed leukemic, immune, and stromal compartments to delineate differentiation trajectories, transcriptional heterogeneity, and microenvironmental remodeling. We also performed in vitro assays to validate ferroptosis resistance, leukemia-T cell dysfunction, and stromal remodeling suggested by the single-cell data.
RESULTS: TP53-mutated AML exhibited a differentiation bias toward granulocyte-monocyte and late myeloid progenitors rather than arrest at the stem cell stage, with enhanced anti-apoptotic and inflammatory programs and a transcriptionally and functionally supported ferroptosis resistance phenotype as a novel hallmark linked to poor prognosis. Functionally, CD8⁺ T cells were predominantly exhausted with an enrichment of dysfunctional subsets and a concomitant reduction of NK cells. B cells showed impaired activation with skewed plasma cell composition, and myeloid cells acquired immunosuppressive features. In the stromal compartment, mesenchymal cells lost hematopoietic and immune-supportive functions and shifted toward osteogenic programs, further reinforcing leukemic survival. We also established an integrated ecosystem score that, together with TP53 mutation burden and mono- versus multi-hit status, captured prognostic heterogeneity and enabled clinical stratification.
CONCLUSIONS: This study provides the first single-cell landscape of de novo TP53-mutated AML, highlighting its reprogrammed leukemic hierarchy and disrupted immune-stromal ecosystem, and offering mechanistic insights and potential therapeutic targets for this high-risk subtype.

Keywords: Adverse prognosis; Bone marrow ecosystem; Ferroptosis resistance; Immune exhaustion; Leukemic hierarchy; Niche remodeling; Single-cell RNA sequencing; TP53-mutated AML

DOI: https://doi.org/10.1186/s40164-026-00751-x