bims-midomi 2026-07-19 papers

J Exp Clin Cancer Res. 2026 Jul 16.

TWIST1 bridges p53 and MDM2 and impairs the efficacy of MDM2 inhibitors.

Sara Piccinin, Bernadetta Szaboova, Flavia Pivetta, Elisa Del Savio, Elena Belli, Simona Gloazzo, Elena Doriguzzi Breatta, Davide Baldazzi, Camillo Rosano, Luca Sigalotti, Roberta Maestro.

BACKGROUND: Tumors that retain wild-type TP53 and rely on MDM2 overexpression to dampen the p53 response were considered prime candidates for therapies based on MDM2 inhibitors (MDM2i). However, clinical trials to date have been disappointing, with limited improvements in progression-free survival, pointing to the existence of intrinsic resistance mechanisms. Building on our previous work demonstrating that TWIST1 attenuates the p53 response in sarcomas, we hypothesized that TWIST1 plays a role in modulating MDM2i efficacy.
METHODS: RNA-sequencing data were integrated with cytotoxicity measurements across a large panel of TP53 wild-type sarcoma cell models. Perturbation experiments were performed using shRNA or CRISPR/Cas9-mediated inhibition, as well as ectopic TWIST1 expression. Cell viability, pathway activation, and transcriptional profile following MDM2i treatment were evaluated in TWIST1-proficient and -deficient models. Co-precipitations, TurboID, molecular docking experiments, and in vitro and in vivo functional assays were employed to characterize the interplay between TWIST1, p53, and MDM2.
RESULTS: TWIST1 expression correlated with reduced sensitivity to multiple MDM2i. TWIST1 inhibition enhanced p53 pathway activation and cell death in response to MDM2i, while TWIST1 overexpression conferred resistance. Mechanistically, we found that TWIST1 directly binds both p53 and MDM2, forming a trimeric complex that facilitates p53:MDM2 interaction, thereby promoting p53 degradation and limiting MDM2i efficacy. Notably, harmine, a compound that promotes TWIST1 degradation, phenocopied the effects of TWIST1 genetic inhibition in augmenting MDM2i sensitivity.
CONCLUSION: TWIST1 confers resistance to MDM2i in TP53 wild-type sarcomas. Targeting TWIST1 restores p53 pathway activation and sensitizes sarcoma cells to MDM2 blockade, establishing TWIST1 as a promising predictive biomarker and therapeutic vulnerability for improving MDM2i efficacy.

Keywords: MDM2 amplification; MDM2 inhibitors; Sarcoma; TWIST1; p53

DOI: https://doi.org/10.1186/s13046-026-03780-w

Oral Maxillofac Surg. 2026 Jul 17. pii: 116. [Epub ahead of print]30(1):

An immunohistochemical based assessment of murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) in jaw osteosarcoma and benign osseous lesions.

Spriha Jha, Aadithya B Urs, Jeyaseelan Augustine, Priya Kumar.

The diagnosis of primary bone tumours of the jaw often presents as a diagnostic dilemma. Overlap in clinical, radiological, and histological features between benign lesions like juvenile trabecular ossifying fibroma (JTOF); osteoblastoma (OB) and malignant tumours like low-grade osteosarcoma (LGOS) makes the diagnosis challenging. While osteosarcoma is a malignant tumour with poor prognosis requiring aggressive treatment, benign lesions have generally favourable outcome. This study aimed to assess the immunohistochemical expression of murine double minute 2 (MDM2) and Cyclin-dependent kinase 4 (CDK4) in low-grade osteosarcoma and benign osseous lesions.
METHODOLOGY: Immunohistochemical analysis was performed on tissue samples from diagnosed cases of LGOS, JTOF, and OB. The expression levels of MDM2 and CDK4 were analysed and compared across the three groups.
RESULTS: We found significantly higher expression of MDM2 and CDK4 in low-grade osteosarcoma compared to JTOF which showed negative expression in all of the cases. Osteoblastoma showed inconsistent and focal positivity contrary to OS where strong and diffuse expression of both the markers was observed. A strong co-expression of both the markers was also noted in 94% of OS cases.
CONCLUSION: Immunohistochemistry for MDM2 and CDK4 is a valuable diagnostic tool in differentiating low-grade osteosarcoma from benign mimics. This approach provides a cost-effective, reliable, and accurate means for diagnosing jaw bone tumours, particularly when tissue samples are insufficient or on small incisional biopsies where accurate diagnosis is of prime importance.

Keywords: Cyclin-dependent kinase 4; Fibroma, ossifying; Immunohistochemistry; Jaw; Osteoblastoma; Osteosarcoma; Proto-oncogene proteins c-mdm2

DOI: https://doi.org/10.1007/s10006-026-01605-w

Int J Mol Sci. 2026 Jun 25. pii: 5725. [Epub ahead of print]27(13):

Harnessing p53 for Proximity Killing.

Joanna E Zawacka.

p53 tumor suppressor evolved as a critical player in navigating the response to environmental stresses such as DNA or oxidative damage and drives cell fate by governing life and death decisions. The p53 protein is encoded by the most commonly mutated gene in human cancers. TP53 gene mutations are associated with worse prognosis and refractory and relapsed disease. The most prevalent mutations are of the missense type and often result in disruption of the DNA-binding capacity and transcription activity. In healthy cells, p53 protein is tightly regulated by its E3 ubiquitin ligase, MDM2 (HDM2), its own transcription target. Mutant p53, therefore, escapes the regulation by the negative feedback loop and is often found upregulated in cancer cells. The efforts to exploit wild-type and mutant p53 for precision oncology have been ongoing in the last two decades yet have not been successful. A recently reported strategy to target TP53-mutant cancers leverages induced proximity, utilizing the high cellular abundance of mutant p53 as a scaffold to concentrate a small-molecule inhibitor against an essential survival protein. This strategy relies on the Regulated Induced Proximity TArgeting Chimera (RIPTAC). Given the recent FDA approval of the first chimeric drug, vepdegestrant, killing by proximity might turn out to be a promising medical advancement for precision oncology.

Keywords: MDM2; MDMX; PROTAC; RIPTAC; TAPTAC; mutant p53; p53; proximity

DOI: https://doi.org/10.3390/ijms27135725

IEEE Trans Comput Biol Bioinform. 2026 Jul 15. PP

Cell-fate Decisions Mediated by Bistability and Oscillations in the p53-AKT-Mdm2 Network.

Yunfeng Zhang, Conghua Wang.

The tumor suppressor p53 plays a central role in stress-response signaling and exhibits crosstalk with the AKT pathway through the AKT-Mdm2 axis. Although this coupling has been linked to cell-fate choices between survival and death, the dynamical basis of these transitions remains unclear. In this paper, we develop a delay-differential equation model of the p53 AKT-Mdm2 network to study how interlocked feedback loops, together with transcriptional-translational delay, shape p53 dy namics. Bifurcation analysis reveals three dynamical regimes that can be linked to distinct cellular outcomes: a stable low p53 equilibrium (pro-survival), sustained p53 oscillations (repair associated dynamics), and a stable high-p53 equilibrium (pro death). We show that the positive feedback generated by p53 dependent inhibition of AKT and AKT-enhanced Mdm2 activity produces bistability within a certain range of total AKT levels. We further find that increasing the delay destabilizes the low-p53 equilibrium and induces oscillations through a Hopf bifurcation. For the baseline parameter setting, a further increase in delay suppresses the oscillatory state and drives the system toward the high-p53 attractor. These results indicate how AKT-dependent bistability and delay-controlled instability jointly organize state transitions in the p53-AKT-Mdm2 circuit.

DOI: https://doi.org/10.1109/TCBBIO.2026.3713926

Front Oncol. 2026 ;16 1877159

Early local recurrence of well-differentiated liposarcoma of the hypopharynx in a young adult: a case report and literature review.

Yi Zhong, Long Chen, Suru Liu, Haiying Sun.

Well-differentiated liposarcoma (WDLPS), also termed atypical lipomatous tumor, is a low-grade malignant adipocytic neoplasm characterized by indolent growth, limited metastatic potential, and a propensity for local recurrence. Primary WDLPS arising in the hypopharyngeal region is exceptionally rare, particularly in young adults, and may clinically mimic benign submucosal lesions. We report the case of a 24-year-old man who presented with a one-month history of persistent foreign body sensation in the throat. Flexible laryngoscopy revealed a smooth submucosal mass arising from the left hypopharyngeal region, and contrast-enhanced magnetic resonance imaging demonstrated a well-circumscribed enhancing lesion without cervical lymphadenopathy. The mass was excised transorally under general anesthesia. Histopathological examination showed mature adipocytic proliferation with atypical stromal cells, and immunohistochemistry demonstrated positivity for MDM2, CDK4, CD34, and p16. Fluorescence in situ hybridization confirmed MDM2 gene amplification, establishing the diagnosis of WDLPS. Although the early postoperative course was uneventful and initial follow-up showed satisfactory mucosal healing, serial laryngoscopic examinations at 2, 2.5, and 4 months after surgery revealed early local recurrence at the surgical site. This case highlights that hypopharyngeal WDLPS can occur in young adults and may recur early even after apparently complete transoral excision. Accurate diagnosis requires integration of histopathology, MDM2/CDK4 immunohistochemistry, and molecular confirmation of MDM2 amplification. Close endoscopic and radiological surveillance is essential for early detection of local recurrence.

Keywords: case report; hypopharynx; laryngoscopy; mdm2 amplification; well-differentiated liposarcoma

DOI: https://doi.org/10.3389/fonc.2026.1877159