bims-p53act 2026-04-19 papers

bims-p53act

Biomed News

on p53 mutations and anti-cancer therapy response

Issue of 2026–04–19
seven papers selected by
Toni Martínez Bernabé, Universitat de les Illes Balears

Suppression of Glucosylceramide Synthase Reverses Drug Resistance in Cancer Cells Harboring Homozygous p53 Mutants.
TP53 mutation landscape and patient survival in oral squamous cell carcinoma.
Quizartinib-induced resistance drives clonal emergence of MV4-11 cells with molecular alterations enabling multidrug antileukemic escape.
Rescuing TP53 from nonsense: novel triazoles for translational readthrough via optimized drug design.
CLL1 polymeric nanoparticles loaded with PI3K/BRD4 dual inhibitor MDP5 and azacitidine as a novel treatment for TP53 mutated acute myeloid leukemia.
p53 Isoforms as Modifiers of the p53-Dependent Responses: A Hidden Code?
Chemotherapy-Induced Oral Mucosal Injury Is Defined by p53 Activation, Cell Cycle Arrest and Diverse Epithelial Progenitor Dynamics.

Int J Mol Sci. 2026 Apr 02. pii: 3237. [Epub ahead of print]27(7):

Suppression of Glucosylceramide Synthase Reverses Drug Resistance in Cancer Cells Harboring Homozygous p53 Mutants.

Md Saqline Mostaq, Mohammad N Amin, Amanda Raphael, Celine Asbury, Anish Gupta, Xin Gu, Xianlin Han, Davorka Sekulic, Pawel Michalak, Lin Kang, Yong-Yu Liu.

  Glucosylceramide synthase (GCS) catalyzes ceramide glycosylation in response to cell stress that produces glucosylceramide and other glycosphingolipids. GCS overexpression is a cause of drug resistance and enriches cancer stem cells (CSCs) during cancer chemotherapy. Previous studies showed that GCS modulates the expression of p53 mutants and oncogenic gain-of-function (GOF) in heterozygous knock-in cell models (TP53 R273H-/+). However, it is unclear whether GCS can modulate the effects of homozygous p53 mutations, which are common in many cancer cases. We report herewith that inhibition of GCS, via UGCG knockout and using an inhibitor (Genz-161), effectively re-sensitizes drug resistance and diminishes CSCs in colon cancer cells carrying the homozygous p53 R273H mutation. In aggressive WiDr cells carrying TP53 R273H mutation, knockout of UGCG gene using CRISPR/Cas9 editing or inhibition of GCS with Genz-161 sensitized cancer cells to oxaliplatin, irinotecan and paclitaxel. With decreased ceramide glycosylation in lipidomic profiling, both UGCG knockout and Genz-161 treatments substantially decreased wound healing, and diminished CSCs and tumor growth under chemotherapy. Interestingly, inhibition of RNA m6A methylation by neplanocin A markedly increased p53 function and reversed drug resistance. Mechanistic investigation revealed that GCS inhibition downregulated methyltransferase-like 3 (METTL3) expression and decreased RNA-m6A modification on mutant p53 R273H effects. Altogether, our findings demonstrate that ceramide glycosylation promotes METTL3 expression and RNA m6A methylation in response to drug-induced stress, thereby promoting mutant p53 expression and associated GOF. Conversely, inhibition of GCS can diminish CSCs and drug resistance via reduction in m6A modification and advance of p53-assocaited tumor suppressive function. GCS inhibition is an achievable approach for mutant cancer treatment.

Keywords:  N6-methyladenosine; RNA modification; cancer stem cells; drug resistance; glucosylceramide synthase; missense mutation; p53 tumor suppressor

DOI:  https://doi.org/10.3390/ijms27073237
Jpn J Clin Oncol. 2026 Apr 14. pii: hyag056. [Epub ahead of print]

TP53 mutation landscape and patient survival in oral squamous cell carcinoma.

Mebae Ichikawa, Yusuke Kondo, Joaquim Carreras, Masashi Sasaki, Shunsuke Nagase, Yasutaka Hoshimoto, Masashi Tamura, Masahiro Uchibori, Takayuki Aoki, Naoya Nakamura, Yohei Masugi, Yoshihide Ota.

   INTRODUCTION: TP53 mutations play a central role in the carcinogenesis of oral squamous cell carcinoma (OSCC). However, due to the diversity of variant patterns of TP53 genetic alterations, the clinical significance of TP53 mutations in OSCC remains poorly understood. Thus, we set out to analyze all exons of the TP53 gene to characterize the TP53 mutation landscape in OSCC and to investigate its associations with clinical outcomes.
METHODS: Treatment-naïve surgical specimens from 124 patients with OSCC were comprehensively analyzed for TP53 mutations using next-generation sequencing. Pathogenicity for each mutation was defined by referring to genomic databases, OncoKB and ClinVar. Multivariable Cox regression analysis was performed to assess the association between the presence of TP53 pathogenic mutations and cancer-specific survival.
RESULTS: TP53 pathogenic mutations were detected in 81/124 (65%) OSCC cases, comprising 75 different variant patterns. OSCC patients harboring TP53 pathogenic mutations showed shorter cancer-specific survival compared to those without pathogenic mutations (multivariable hazard ratio, 3.70; 95% confidence interval, 1.08-12.61). Moreover, cases with truncating and/or splice mutations showed worse outcomes than other mutation types. Among OSCC patients with stage III/IV, the presence of TP53 pathogenic mutations was significantly associated with shorter survival (P = 0.001), whereas no such association was observed in stage I/II patients (P = 0.89).
CONCLUSIONS: TP53 pathogenic mutations in OSCC have been associated with shorter cancer-specific survival, especially for advanced diseases. Our findings likely attest to the importance of TP53-based molecular classification, leading to the development of novel precision strategies against OSCC.

Keywords:  next-generation sequencing; oral cancer; p53; pathogenic mutation; prognosis

DOI:  https://doi.org/10.1093/jjco/hyag056
Eur J Pharmacol. 2026 Apr 15. pii: S0014-2999(26)00359-6. [Epub ahead of print] 178877

Quizartinib-induced resistance drives clonal emergence of MV4-11 cells with molecular alterations enabling multidrug antileukemic escape.

Livia Bassani Lins de Miranda, Keli Lima, Diego A Pereira-Martins, Juan Luiz Coelho-Silva, Victoria Tomaz, Luiz Gustavo Ferreira Cortez, Marina de Franca Basto Silva, Rafael Lucas Muniz Guedes, Paulo Vidal Campregher, Dominique Sternadt, Eduardo Magalhães Rego, Fabiola Traina, Jan Jacob Schuringa, João Agostinho Machado-Neto.

  FLT3 inhibitors have become a cornerstone in the treatment of FLT3-mutated acute myeloid leukemia (AML), however, durable clinical responses are frequently limited by the emergence of acquired resistance. In this study, we established and comprehensively characterized a quizartinib-resistant FLT3-ITD AML model to elucidate the molecular and functional mechanisms underlying therapeutic failure. Prolonged exposure of MV4-11 cells to escalating concentrations of quizartinib resulted in the selection of quizartinib resistant clones (MV4-11QR), displaying an increase in IC50 and a shift from cytotoxic to predominantly cytostatic responses. Resistant cells maintained MAPK signaling despite FLT3 inhibition. Global proteomic profiling revealed extensive reprogramming, with enrichment of pathways related to energy metabolism, RNA processing, and translational regulation, accompanied by enhanced mitochondrial respiration and glycolytic capacity. Whole-genome sequencing identified acquisition of the FLT3D835H mutation and clonal expansion of TP53R248W with loss of the wild-type TP53 allele, indicating strong treatment-driven clonal selection. Functionally, MV4-11QR cells showed broad cross-resistance to clinically relevant agents, including midostaurin, venetoclax, and cytarabine. Importantly, pharmacological targeting of mutant p53 with eprenetapopt or MAPK signaling with trametinib restored sensitivity to quizartinib, inducing synergistic or additive cytotoxic effects and increased apoptosis. Together, these findings define a multilayered resistance program involving genetic, signaling, and metabolic adaptations and support rational combination strategies to overcome FLT3 inhibitor resistance in AML.

Keywords:  Acute myeloid leukemia; Clonal selection; FLT3 inhibitor resistance; Multidrug resistance; Quizartinib; TP53 mutation

DOI:  https://doi.org/10.1016/j.ejphar.2026.178877
Sci Rep. 2026 Apr 15.

Rescuing TP53 from nonsense: novel triazoles for translational readthrough via optimized drug design.

Davide Ricci, Michele Menditto, Giulia Culletta, Marco Tutone, Carla Rizzo, Andrea Pace, Laura Lentini, Ivana Pibiri.

  Nonsense mutations introduce premature termination codons (PTCs), leading to mRNA degradation and the production of truncated, non-functional proteins. These mutations account for approximately 10% of TP53 alterations, a key driver in over 50% human cancers. Effective therapeutic strategies to restore full-length functional p53 remain limited. Here, using an optimized drug design workflow that integrates in silico approaches, we identified and characterized a novel class of 1,2,4-triazole-based translational readthrough-inducing drugs (TRIDs) capable of restoring full-length p53 protein in cells harboring the R213X nonsense mutation. We synthesized and screened four compounds (IP14, IP15, IP17, IP18) with favorable in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. All four compounds successfully rescued p53 expression in H1299 R213X cells, outperforming Ataluren and matching G418 at significantly lower concentrations. The restored p53 exhibited nuclear localization upon genotoxic stress and induced transcription of canonical targets. These findings highlight the therapeutic potential of these compounds for treating TP53 nonsense mutations in cancer and lay the groundwork for the development of targeted nonsense mutation-specific treatment for a wide range of pathologies, including new emergent p53 related diseases.

Keywords:  Cancer; Computer aided drug design; Nonsense mutations; P53; Translational readthrough; Triazoles

DOI:  https://doi.org/10.1038/s41598-026-48790-y
Int J Pharm. 2026 Apr 10. pii: S0378-5173(26)00280-2. [Epub ahead of print]697 126832

CLL1 polymeric nanoparticles loaded with PI3K/BRD4 dual inhibitor MDP5 and azacitidine as a novel treatment for TP53 mutated acute myeloid leukemia.

Qiaoyu Pan, Fei Yang, Ajaykumar Chittipolu, Raghu Ramanathan, Yuxiang Dong, R Katherine Hyde, Vijaya R Bhatt, Ram I Mahato.

  Acute myeloid leukemia (AML) in older adults, particularly with mutation in the tumor suppressor gene TP53, has high rates of resistance to standard chemotherapy regimens, often resulting in patients death within months of diagnosis. To address this unmet need, we investigated the therapeutic potential of targeted nanoparticles (NPs) loaded with MDP5 (our novel BRD4/PI3K dual inhibitor) and azacitidine (AZA), a standard-of-care hypomethylating agent. A combination of MDP5 and AZA demonstrated synergistic inhibitory effects in both TP53 wild-type and TP53-mutant AML cell lines, and downregulated expression levels of MYC, BCL-2, and CDK6. To improve delivery, we developed a novel AZA-conjugated polymer, mPEG113-p(Asp-BLA)-p(Asp-AZA)-g-p(Asp-DA), which self-assembles into NPs. C-type lectin-like molecule-1 (CLL1) is highly expressed on leukemic blasts and leukemia stem cells (LSCs) but not universally across all AML subtypes. To leverage this selective targeting, we modified NPs with a peptide that recognizes CLL-1. The CLL-1 targeted NPs loaded with MDP5 and AZA demonstrated superior AML control and targeting of LSCs in TP53-mutant mice models, while sparing normal hematopoiesis in healthy NSG mice. These promising results highlight a potential efficacy of our novel CLL-1 targeted NP combination approach to treat AML, particularly those harboring TP53 mutation.

Keywords:  Acute myeloid leukemia; BRD4/PI3K inhibitor; CLL1; Nanoparticle; TP53 mutation

DOI:  https://doi.org/10.1016/j.ijpharm.2026.126832
Cancers (Basel). 2026 Mar 25. pii: 1057. [Epub ahead of print]18(7):

p53 Isoforms as Modifiers of the p53-Dependent Responses: A Hidden Code?

Laura Bartolomei, Beatrice Pretto, Samuele Brugnara, Alessandra Sontacchi, Vanessa Dassi, Aya Bousrih, Chiara Damaggio, Francesca Flangini, Alessandra Bisio, Yari Ciribilli.

  The tumor suppressor protein p53, encoded by the TP53 gene, is known as the "Guardian of the Genome", and alterations in TP53 are common to more than 50% of human cancers. p53 is a critical regulator of cellular responses to several stress conditions, such as DNA damage, oncogene activation, and nutrient starvation. p53 was traditionally described as a single transcription factor; however, now it is recognized as a complex family of isoforms generated through alternative promoter usage, alternative splicing, and alternative initiation of translation. These processes give rise to at least 12 distinct p53 isoforms in humans, including p53α (the canonical full-length isoform), p53β, p53γ, Δ40p53, Δ133p53, and Δ160p53, each with unique structural and functional properties. p53 isoforms differ in the presence or absence of specific and fundamental domains located both at N- and C-terminal ends, determining an altered DNA-binding potential, transcriptional activity, and protein-protein interactions. For instance, Δ133p53 isoforms lack part of the N-terminal domains and can exert dominant-negative effects over full-length p53α or modulate alternative transcriptional programs. Similarly, p53β and p53γ isoforms, which have a unique C-termini, influence cellular senescence. The expression patterns of p53 isoforms are tissue-specific and dynamically regulated under both physiological as well as pathological conditions. Alterations of isoform balance have been involved in tumor progression, metastasis, and therapy resistance. Importantly, specific isoforms can either enhance or limit canonical p53 tumor suppressor functions, thereby contributing to the functional diversity of the p53 network. Overall, the p53 isoform landscape adds a critical layer of complexity to p53 biology. In this review, we summarize the mechanisms underlying the production of p53 isoforms, their functions, and their expression in cancer, with the idea that a better understanding of the differential regulation and functional interplay of p53 isoforms may provide novel biomarkers and therapeutic targets in cancer.

Keywords:  TP53; cancer aggressiveness; cancer biomarkers; gene expression; p53 isoforms

DOI:  https://doi.org/10.3390/cancers18071057
bioRxiv. 2026 Apr 09. pii: 2026.04.06.716752. [Epub ahead of print]

Chemotherapy-Induced Oral Mucosal Injury Is Defined by p53 Activation, Cell Cycle Arrest and Diverse Epithelial Progenitor Dynamics.

Pedro H F Silva, Lu Li, Madison Muriel, Tara Brennan, Md Hasanuzzaman, Mariadela Demoura, Joleene Stampfer, Michele Sveinsson, Christos Fountzilas, Jill E Schabert, Anurag K Singh, Jonathan E Bard, Nicolas F Schlecht, Laertis Ikonomou, Patricia I Diaz.

Chemotherapy-induced oral mucositis is a common and debilitating complication, yet the mechanisms underlying oral mucosa injury and repair remain poorly defined. Using a mouse model of 5-fluorouracil (5-FU)-induced mucositis, we define gene networks and oral mucosal cellular landscape dynamics in response to chemotoxic stress. We show that 5-FU-induced epithelial atrophy is driven primarily by cell cycle arrest rather than apoptosis, despite concurrent activation of p53-dependent transcriptional programs linked to both cell fates within individual cells. Relative to intestine, the recovering oral mucosa exhibits a more effective cell cycle checkpoint response and uniquely undergoes metabolic reprogramming toward lipid oxidation. Single-cell RNA sequencing revealed putative epithelial progenitor populations with distinct responses to chemotherapy, including chemoresistant cells with a p53- and AP-1 complex gene signature, reminiscent of lung transitional cell states. These findings define diverse progenitor dynamics and p53-driven responses as key determinants of oral mucosal injury and repair following chemotherapy.

DOI: https://doi.org/10.64898/2026.04.06.716752