bims-midomi 2025-08-17 papers

Cells. 2025 Jul 22. pii: 1126. [Epub ahead of print]14(15):

The Role of Nuclear Phosphoinositides in the p53-MDM2 Nexus.

Jeong Hyo Lee, Muhammad Khalil Salah, Xiangqin Chen, Nickolas Vladimir Kucherenko, Vincent L Cryns, Richard A Anderson.

Recent insights into the p53-MDM2 nexus have advanced deeper understanding of their regulation and potent impact on cancer heterogeneity. The roles of nuclear phosphoinositide (PIPns) in modulating this pathway are emerging as a key mechanism. Here, we dissect the molecular mechanisms by which nuclear PIPns stabilize p53 through the recruitment of small heat shock proteins (sHSPs), activate the nuclear phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascade, and modulate MDM2 function to regulate the p53-MDM2 interaction. We propose potential mechanisms by which nuclear PIPns coordinate signaling with nuclear p53, AKT, and MDM2. Ultimately, we highlight that nuclear PIPns serve as a 'third messenger' within the p53-MDM2 axis, expanding the current framework of non-canonical nuclear signaling in cancer biology.

Keywords: AKT; MDM2; nucleus; p53; phosphoinositide; small heat shock protein

DOI: https://doi.org/10.3390/cells14151126

Clin Cancer Res. 2025 Aug 11.

Milademetan in advanced solid tumors with MDM2 amplification and wild-type TP53: pre-clinical and phase 2 clinical trial results.

PURPOSE: MDM2 is an E3 ubiquitin ligase that degrades the tumor suppressor p53. In cancers, MDM2 amplification (MDM2amp) leads to overexpression of MDM2, inducing p53 degradation and a p53-null phenotype even in the absence of TP53 mutations. We report here the pre-clinical and clinical activity of milademetan, a potent and selective oral small molecule inhibitor of the MDM2-p53 interaction, in MDM2amp, TP53-wildtype (wt) solid tumors.
PATIENTS AND METHODS: Milademetan was tested against a variety of cell-line and xenograft tumor models. This supported a phase II basket study (MANTRA-2) in patients with advanced MDM2amp, TP53-wt solid tumors. The primary endpoint was objective response rate (ORR), and key secondary endpoints included progression-free survival (PFS) and adverse events.
RESULTS: Milademetan showed potent activity against MDM2amp, TP53-wt laboratory models. In the phase II trial, 40 patients received milademetan, of whom 31 had centrally confirmed molecular testing. The best overall response was 19.4% (6/31) with 1 confirmed response (3.2%) and 5 unconfirmed partial responses, including a patient with endometrial stromal sarcoma who achieved 100% target lesion reduction. The median PFS was 3.5 months (95% CI:1.8, 3.7). Grade 3 or 4 adverse events observed included thrombocytopenia, neutropenia, anemia, leukopenia, and diarrhea.
CONCLUSION: Milademetan had a manageable safety profile and achieved responses against a variety of refractory MDM2amp, TP53 -wt solid tumors, but tumor reductions were short-lived. Subsequent MDM2 inhibitor efforts should focus on combination strategies or treatment in earlier lines of therapy to achieve more durable clinical benefit.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0762

Transl Lung Cancer Res. 2025 Jul 31. 14(7): 2571-2583

Prognostic implications of MDM2 expression in surgically resected epidermal growth factor receptor mutant lung cancer with pathological lymph node metastasis.

Tetsuya Isaka, Yohei Miyagi, Rika Kasajima, Kota Washimi, Shuji Murakami, Haruhiro Saito, Yui Sueishi, Naoko Shigeta, Ikki Takada, Ryotaro Matsuyama, Chiaki Kanno, Takuya Nagashima, Hiroyuki Ito.

Background: MDM2 protein regulates p53 protein activity; however, the prognostic impact of MDM2 expression in primary lung cancer on patient prognoses is unknown. This study investigated the prognostic implications of MDM2 protein expression among patients with epidermal growth factor receptor mutant (EGFRm) lung adenocarcinoma with pathologic lymph node metastases after surgery.
Methods: Immunohistochemical analysis was conducted to determine the MDM2 expression of pN1-N2 EGFRm [exon 19 deletion mutation (Ex19) and exon 21 L858R mutation (Ex21)] lung cancer that were surgically resected between January 2010 and December 2020 (n=124). The postoperative prognosis and cumulative incidence of recurrence were retrospectively analyzed.
Results: MDM2 protein expression was positive in 56 patients (45.2%) with EGFRm lung adenocarcinoma. The relapse-free survival (RFS) rate was significantly better among patients with MDM2+ vs. those with MDM2- (5-year RFS: 35.5% vs. 14.8%, P=0.04). Multivariable analysis revealed MDM2+ as an independent favorable prognostic factor for RFS [hazard ratio (HR), 0.64; 95% confidence interval (CI): 0.42-0.98; P=0.04]. Among patients with Ex21 lung cancer (n=63), significantly better RFS and overall survival (OS) were seen in patients with MDM2+ than those with MDM2- (5-year RFS: 36.4% vs. 9.2%, P=0.005; 5-year OS: 81.8% vs. 39.3%, P=0.002). Multivariable analysis revealed that among patients with Ex21 lung cancer, MDM2+ was an independent favorable prognostic factor for RFS (HR, 0.43; 95% CI: 0.23-0.80; P=0.008) and OS (HR, 0.32; 95% CI: 0.15-0.67; P=0.003), and it was also associated with a low cumulative incidence of overall distant recurrence (HR, 0.42; 95% CI: 0.20-0.87; P=0.02) and central nervous system recurrence (HR, 0.23; 95% CI: 0.07-0.80; P=0.02).
Conclusions: MDM2 protein expression is a prognostic predictor of RFS and OS in patients with pN1-N2 Ex21 lung cancer after curative surgery. MDM2 can be a novel biomarker for predicting postoperative prognosis and distant metastasis, especially in the central nervous system.

Keywords: EGFR gene mutation; MDM2; distant metastasis; overall survival (OS); recurrence-free survival (RFS)

DOI: https://doi.org/10.21037/tlcr-2025-143