bims-midomi 2026-02-08 papers

ESMO Gastrointest Oncol. 2025 Jun;8 100187

MDM2 amplification in a real-world cohort of patients with biliary tract cancer from the Spanish RETUD gastrointestinal registry.

A J Muñoz Martín, F Castet, J Soto Alsar, J Adeva, P Peinado, B Graña, I Alés Díaz, R M Rodríguez-Alonso, M Lobo de Mena, R Vera, I Ruiz de Mena, S Aguilar, S Vega, L Ortega Morán, T Macarulla.

Background: Antagonist of mouse double minute 2 homolog (MDM2) represents a novel therapeutic strategy in biliary tract cancer (BTC). We aimed to characterize the epidemiology of MDM2 amplifications in patients with BTC, associations of MDM2 with other genetic alterations, and survival outcomes.
Materials and methods: A real-world cohort of patients diagnosed with BTC (1 January 2017 to 31 December 2022) was evaluated (RETUD NCT06711211). Next-generation sequencing (NGS) testing was carried out. Demographic and clinical characteristics, molecular profile, treatments, and effectiveness [overall response rate (ORR) and survival outcomes] were assessed. Progression-free survival (PFS), overall survival (OS), and ORR were estimated for patients receiving first-line therapy, using the Kaplan-Meier method. Descriptive analyses were used to assess demographic, clinical, and molecular features.
Results: A total of 301 patients were included. MDM2 amplification was reported in 19 patients (6.3%); two of them (10.5%) had TP53 mutations. Most patients (63.2%; 12/19) with MDM2 amplification had intrahepatic tumors. However, MDM2 amplification was more frequent in patients with gall-bladder carcinoma (12.9%; 4/31). Patients with/without MDM2 amplification receiving first-line therapy [cisplatin and gemcitabine (CisGem)] showed a median OS [95% confidence interval (CI)] of 18.4 months (12.3-19.9 months) and 17.8 months (12.3-19.9 months, P = 0.247), a median PFS (95% CI) of 5.3 months (2.7-8.9 months) and 6.0 months (5.3-6.8 months, P = 0.423), and an ORR of 21.4% and 29.6% (P = 0.762), respectively.
Conclusions: Incidence of MDM2 amplification was similar to that described in other BTC cohorts. Comparable results in demographic/clinical characteristics, molecular profile, and survival outcomes between patients with/without MDM2 amplification was observed.

Keywords: MDM2 amplification; RETUD registry; Spain; biliary tract cancer; real-world data

DOI: https://doi.org/10.1016/j.esmogo.2025.100187

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

Cell Death Differ. 2026 Jan 30.

Identification of MKRN1 as a key modulator of the p53-MDM2 feedback loop.

Tatsuya Shimada, Takuya Noguchi, Ryuto Komatsu, Kohei Otani, Takaya Komatsu, Sara Suzuki, Maki Mitsuya, Takumi Okubo, Ryo Ito, Mayuka Yamada, Yusuke Hirata, Atsushi Matsuzawa.

The p53-murine double minute 2 (MDM2) feedback loop plays a central role in tumor suppression by optimizing p53-dependent DNA damage responses (DDRs), though it has been suggested that factors other than MDM2 are also involved in the regulation of the p53-MDM2 feedback loop. We identified makorin ring finger protein 1 (MKRN1) as a novel ubiquitin E3 ligase that ubiquitinates MDM2 and thereby promotes the p53 activation. As previously demonstrated, MKRN1 ubiquitinates and degrades p53 under steady-state conditions. However, when DNA damage occurs, MKRN1 switches its substrate to MDM2. Thereafter, MKRN1 promotes the stabilization and activation of p53 through proteasomal degradation of MDM2, which contributes to the elimination of DNA-damaged cells. Moreover, we found that the switch in the substrate of MKRN1 was determined by the NAD(+)-dependent protein deacetylase Sirtuin-1 (SIRT1). Thus, our results suggest that MKRN1 working in conjunction with SIRT1 is a master regulator of the p53-MDM2 feedback loop modulated by crosstalk between ubiquitination and acetylation.

DOI: https://doi.org/10.1038/s41418-026-01662-4